MicroRNA-Based Methods and Compositions for the Diagnosis, Prognosis and Treatment of Breast Cancer

The present invention provides novel methods and compositions for the diagnosis, prognosis and treatment of breast cancer. The invention also provides methods of identifying anti-breast cancer agents.

Skip to: Description  ·  Claims  · Patent History  ·  Patent History
Description
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 14/145,364 filed Dec. 31, 2013, still pending, which is a divisional application of U.S. Ser. No. 12/012,235, filed Jan. 31, 2008, now U.S. Pat. No. 8,658,370 issued Feb. 25, 2014, which entered the National Phase on Jan. 31, 2008, from the International PCT Application No. U.S. Ser. No. 06/029,889, filed Jul. 31, 2006, which claims the benefit of U.S. Provisional Application No. 60/704,464, filed Aug. 1, 2005. The disclosures of each of the aforementioned applications are incorporated herein by reference for all purposes.

GOVERNMENT SUPPORT

This invention was supported by a grant under Program Project Grant P01CA76259, P01CA81534, and P30CA56036 from the National Cancer Institute. The Government has certain rights in this invention.

BACKGROUND OF THE INVENTION

Breast cancer is a significant health problem for women in the United States and throughout the world. Although advances have been made in the detection and treatment of the disease, breast cancer remains the second leading cause of cancer-related deaths in women, affecting more than 180,000 women in the United States each year. For women in North America, the life-time odds of getting breast cancer are now one in eight.

No universally successful method for the treatment or prevention of breast cancer is currently available. Management of breast cancer currently relies on a combination of early diagnosis (for example, through routine breast screening procedures) and aggressive treatment, which may include one or more of a variety of treatments, such as surgery, radiotherapy, chemotherapy and hormone therapy. The course of treatment for a particular breast cancer is often selected based on a variety of prognostic parameters including an analysis of specific tumor markers.

Although the discovery of BRCA1 and BRCA2 were important steps in identifying key genetic factors involved in breast cancer, it has become clear that mutations in BRCA1 and BRCA2 account for only a fraction of inherited susceptibility to breast cancer. In spite of considerable research into therapies for breast cancer, breast cancer remains difficult to diagnose and treat effectively, and the high mortality observed in breast cancer patients indicates that improvements are needed in the diagnosis, treatment and prevention of the disease.

MicroRNAs are a class of small, non-coding RNAs that control gene expression by hybridizing to and triggering either translational repression or, less frequently, degradation of a messenger RNA (mRNA) target. The discovery and study of miRNAs has revealed miRNA-mediated gene regulatory mechanisms that play important roles in organismal development and various cellular processes, such as cell differentiation, cell growth and cell death. Recent studies suggest that aberrant expression of particular miRNAs may be involved in human diseases, such as neurological disorders and cancer. In particular, misexpression of miR-16-1 and/or miR-15a has been found in human chronic lymphocytic leukemias.

The development and use of microarrays containing all known human microRNAs has permitted a simultaneous analysis of the expression of every miRNA in a sample. These microRNA microarrays have not only been used to confirm that miR-16-1 is deregulated in human CLL cells, but also to generate miRNA expression signatures that are associated with well-defined clinico-pathological features of human CLL.

The use of microRNA microarrays to identify a group of microRNAs, which are differentially-expressed between normal cells and breast cancer cells (for example, an expression signature or expression profile), may help pinpoint specific miRNAs that are involved in breast cancer. Furthermore, the identification of putative targets of these miRNAs may help to unravel their pathogenic role. The present invention provides novel methods and compositions for the diagnosis, prognosis and treatment of breast cancer.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the identification of a breast cancer-specific signature of miRNAs that are differentially-expressed in breast cancer cells, relative to normal control cells.

Accordingly, embodiments of the invention encompass methods of diagnosing whether a subject has, or is at risk for developing, breast cancer, comprising measuring the level of at least one miR gene product in a test sample from the subject and comparing the level of the miR gene product in the test sample to the level of a corresponding miR gene product in a control sample. An alteration (for example, an increase, a decrease) in the level of the miR gene product in the test sample, relative to the level of a corresponding miR gene product in a control sample, is indicative of the subject either having, or being at risk for developing, breast cancer. In certain embodiments, the at least one miR gene product is selected from the group consisting of miR-125b-1, miR125b-2, miR-145, miR-21, miR-155, miR-10b and combinations thereof.

The level of the at least one miR gene product can be measured using a variety of techniques that are well known to those of skill in the art. In one embodiment, the level of the at least one miR gene product is measured using Northern blot analysis. In another embodiment, the level of the at least one miR gene product is measured by reverse transcribing RNA from a test sample obtained from the subject to provide a set of target oligodeoxynucleotides, hybridizing the target oligodeoxynucleotides to a microarray that comprises miRNA-specific probe oligonucleotides to provide a hybridization profile for the test sample, and comparing the test sample hybridization profile to a hybridization profile generated from a control sample. An alteration in the signal of at least one miRNA in the test sample relative to the control sample is indicative of the subject either having, or being at risk for developing, breast cancer. In a particular embodiment, the microarray comprises miRNA-specific probe oligonucleotides for a substantial portion of the human miRNome. In a further embodiment, the microarray comprises miRNA-specific probe oligonucleotides for one or more miRNAs selected from the group consisting of miR-145, miR-21, miR-155, miR-10b, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, miR-213, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, let-7i (let-7d-v2), miR-101-1, miR-122a, miR-128b, miR-136, miR-143, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-205, miR-206, miR-210 and combinations thereof.

Embodiments of the invention also provide methods of diagnosing a breast cancer associated with one or more prognostic markers, comprising measuring the level of at least one miR gene product in a breast cancer test sample from a subject and comparing the level of the at least one miR gene product in the breast cancer test sample to the level of a corresponding miR gene product in a control sample. The breast cancer can be associated with one or more adverse prognostic markers associated with breast cancer, such as, but not limited to, estrogen receptor expression, progesterone receptor expression, positive lymph node metastasis, high proliferative index, detectable p53 expression, advanced tumor stage, and high vascular invasion. In one embodiment, the level of the at least one miR gene product is measured by reverse transcribing RNA from a test sample obtained from the subject to provide a set of target oligodeoxynucleotides, hybridizing the target oligodeoxynucleotides to a microarray that comprises miRNA-specific probe oligonucleotides to provide a hybridization profile for the test sample, and comparing the test sample hybridization profile to a hybridization profile generated from a control sample. An alteration in the signal of at least one miRNA in the test sample relative to the control sample is indicative of the subject either having, or being at risk for developing, a breast cancer associated with the one or more prognostic markers. In a particular embodiment, the microarray comprises at least one miRNA-specific probe oligonucleotide for a miRNA selected from the group consisting of miR-26a, miR-26b, miR-102 (miR-29b), miR-30a-5p, miR-30b, miR-30c, miR-30d, miR-185, miR-191, miR-206, miR-212, let-7c, miR-9-2, miR-15-a, miR-21, miR-30a-s, miR-133a-1, miR-137, miR-153-2, miR-154, miR-181a, miR-203, miR-213, let-7f-1, let-7a-3, let-7a-2, miR-9-3, miR-10b, miR-27a, miR-29a, miR-123, miR-205, let-7d, miR-145, miR-16a, miR-128b and combinations thereof.

Embodiments of the invention also encompass methods of treating breast cancer in a subject, wherein at least one miR gene product is de-regulated (for example, down-regulated, up-regulated) in the cancer cells of the subject. When the at least one isolated miR gene product is down-regulated in the breast cancer cells, the method comprises administering an effective amount of the at least one isolated miR gene product, such that proliferation of cancer cells in the subject is inhibited. In one embodiment, the method comprises administering an effective amount of the at least one isolated miR gene product, provided that the miR gene is not miR-15a or miR-16-1, such that proliferation of cancer cells in the subject is inhibited. When the at least one isolated miR gene product is up-regulated in the cancer cells, the method comprises administering to the subject an effective amount of at least one compound for inhibiting expression of the at least one miR gene, such that proliferation of breast cancer cells is inhibited.

In related embodiments, the invention provides methods of treating breast cancer in a subject, comprising determining the amount of at least one miR gene product in breast cancer cells from the subject, relative to control cells. If expression of the miR gene product is deregulated in breast cancer cells, the methods further comprise altering the amount of the at least one miR gene product expressed in the breast cancer cells. If the amount of the miR gene product expressed in the cancer cells is less than the amount of the miR gene product expressed in control cells, the method comprises administering an effective amount of at least one isolated miR gene product. In one embodiment, the miR gene product is not miR-15a or miR-16-1. If the amount of the miR gene product expressed in the cancer cells is greater than the amount of the miR gene product expressed in control cells, the method comprises administering to the subject an effective amount of at least one compound for inhibiting expression of the at least one miR gene. In one embodiment, the miR gene product is not miR-15a or miR-16-1.

The invention further provides pharmaceutical compositions for treating breast cancer. In one embodiment, the pharmaceutical compositions comprise at least one isolated miR gene product and a pharmaceutically-acceptable carrier. In a particular embodiment, the at least one miR gene product corresponds to a miR gene product that has a decreased level of expression in breast cancer cells relative to suitable control cells. In certain embodiments the isolated miR gene product is selected from the group consisting of miR-145, miR-10b, miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, miR-101-1, miR-143 and combinations thereof.

In another embodiment, the pharmaceutical compositions of the invention comprise at least one miR expression inhibition compound. In a particular embodiment, the at least one miR expression inhibition compound is specific for a miR gene whose expression is greater in breast cancer cells than control cells. In certain embodiments, the miR expression inhibition compound is specific for one or more miR gene products selected from the group consisting of miR-21, miR-155, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-213, let-7i (let-7d-v2), miR-122a, miR-128b, miR-136, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210, miR-213 and combinations thereof.

Embodiments of the invention also encompass methods of identifying an anti-breast cancer agent, comprising providing a test agent to a cell and measuring the level of at least one miR gene product in the cell. In one embodiment, the method comprises providing a test agent to a cell and measuring the level of at least one miR gene product associated with decreased expression levels in breast cancer cells. An increase in the level of the miR gene product in the cell, relative to a suitable control cell, is indicative of the test agent being an anti-breast cancer agent. In a particular embodiment, the at least one miR gene product associated with decreased expression levels in breast cancer cells is selected from the group consisting of miR-145, miR-10b, miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, miR-101-1, miR-143 and combinations thereof.

In other embodiments the method comprises providing a test agent to a cell and measuring the level of at least one miR gene product associated with increased expression levels in breast cancer cells. A decrease in the level of the miR gene product in the cell, relative to a suitable control cell, is indicative of the test agent being an anti-breast cancer agent. In a particular embodiment, at least one miR gene product associated with increased expression levels in breast cancer cells is selected from the group consisting of miR-21, miR-155, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-213, let-7i (let-7d-v2), miR-122a, miR-128b, miR-136, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210, miR-213 and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

FIG. 1 depicts a tree generated by cluster analysis showing a separation of breast cancer from normal tissues on the basis of differential microRNA expression (P<0.05). The bar at the bottom of the figure indicates the group of cancer (red) or normal breast tissues (yellow).

FIG. 2 is a graph depicting the probability (0.0 to 1.0) of each sample being a cancerous or normal tissue based on PAM analysis. All breast cancer and normal tissues were correctly predicted by the miR signature shown in Table 2.

FIG. 3A is a Northern blot depicting the expression level of miR-125b, using a miR-125b complementary probe, in a normal sample, as well as several tumor samples from breast cancer patients (P). The U6 probe was used for normalization of expression levels for each sample.

FIG. 3B is a Northern blot depicting the expression level of miR-145, using a miR-145 complementary probe, in a normal sample, as well as several tumor samples from breast cancer patients (P). The U6 probe was used for normalization of expression levels for each sample.

FIG. 3C is a Northern blot depicting the expression level of miR-21, using a miR-21 complementary probe, in a normal sample, as well as several tumor samples from breast cancer patients (labeled as numbered patients). The U6 probe was used for normalization of expression levels for each sample.

FIG. 3D is a Northern blot depicting the expression levels of microRNAs miR-125b, miR-145 and miR-21 in various breast cancer cell lines. The expression level of each microRNA was also determined in a sample from normal tissues. The U6 probe was used for normalization of expression levels for each sample.

FIG. 4A is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with the presence (ER+) or absence (ER−) of estrogen receptor.

FIG. 4B is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with the presence (PR+) or absence (PR−) of progesterone receptor.

FIG. 4C is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with stage 1 (pT1) or stage 2 or 3 (pT2-3) tumors.

FIG. 4D is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with the presence (pN0) or absence (pN10+) of lymph node metastasis.

FIG. 4E is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with the presence or absence of vascular invasion.

FIG. 4F is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with a high (MIB-1>30) or low (MIB-1<20) proliferative index (PI).

FIG. 4G is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with positive (p53+) or negative (p53−) immunostaining of p53.

 DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, in part, on the identification of particular miRNAs whose expression is altered in breast cancer cells relative to normal control cells, and microRNAs whose expression is altered in breast cancer cells associated with particular prognostic features, relative to breast cancer cells lacking such features.

As used herein interchangeably, a “miR gene product,” “microRNA,” “miR,” or “miRNA” refers to the unprocessed or processed RNA transcript from an miR gene. As the miR gene products are not translated into protein, the term “miR gene products” does not include proteins. The unprocessed miR gene transcript is also called an “miR precursor,” and typically comprises an RNA transcript of about 70-100 nucleotides in length. The miR precursor can be processed by digestion with an RNAse (for example, Dicer, Argonaut, or RNAse III, for example, E. coli RNAse III)) into an active 19-25 nucleotide RNA molecule. This active 19-25 nucleotide RNA molecule is also called the “processed” miR gene transcript or “mature” miRNA.

The active 19-25 nucleotide RNA molecule can be obtained from the miR precursor through natural processing routes (for example, using intact cells or cell lysates) or by synthetic processing routes (for example, using isolated processing enzymes, such as isolated Dicer, Argonaut, or RNAase III). It is understood that the active 19-25 nucleotide RNA molecule can also be produced directly by biological or chemical synthesis, without having been processed from the miR precursor.

The sequences of 187 miR gene products are provided in Table 1. All nucleic acid sequences herein are given in the 5′ to 3′ direction. In addition, genes are represented by italics, and gene products are represented by normal type; for example, mir-17 is the gene and miR-17 is the gene product.

The present invention encompasses methods of diagnosing whether a subject has, or is at risk for developing, breast cancer, comprising measuring the level of at least one miR gene product in a test sample from the subject and comparing the level of the miR gene product in the test sample to the level of a corresponding miR gene product in a control sample. As used herein, a “subject” can be any mammal that has, or is suspected of having, breast cancer. In a particular embodiment, the subject is a human who has, or is suspected of having, breast cancer.

The breast cancer can be any form of breast cancer and may be associated with one or more prognostic markers or features, including, but not limited to, estrogen receptor expression, progesterone receptor expression, lymph node metastasis, high proliferative index, detectable p53 expression, advanced tumor stage, and high vascular invasion. The prognostic marker can be associated with an adverse or negative prognosis, or it may be associated with a good or positive prognosis.

TABLE 1 Human miR Gene Product Sequences Precursor Sequence SEQ ID Name (5′ to 3′)* NO. hsa-let- CACTGTGGGATGAGGTAGTAGGTT 1 7a-1-prec GTATAGTTTTAGGGTCACACCCAC CACTGGGAGATAACTATACAATCT ACTGTCTTTCCTAACGTG hsa-let- AGGTTGAGGTAGTAGGTTGTATAG 2 7a-2-prec TTTAGAATTACATCAAGGGAGATA ACTGTACAGCCTCCTAGCTTTCCT hsa-let- GGGTGAGGTAGTAGGTTGTATAGT 3 7a-3-prec TTGGGGCTCTGCCCTGCTATGGGA TAACTATACAATCTACTGTCTTTC CT hsa-let- GTGACTGCATGCTCCCAGGTTGAG 4 7a-4-prec GTAGTAGGTTGTATAGTTTAGAAT TACACAAGGGAGATAACTGTACAG CCTCCTAGCTTTCCTTGGGTCTTG CACTAAACAAC hsa-let- GGCGGGGTGAGGTAGTAGGTTGTG 5 7b-prec TGGTTTCAGGGCAGTGATGTTGCC CCTCGGAAGATAACTATACAACCT ACTGCCTTCCCTG hsa-let- GCATCCGGGTTGAGGTAGTAGGTT 6 7c-prec GTATGGTTTAGAGTTACACCCTGG GAGTTAACTGTACAACCTTCTAGC TTTCCTTGGAGC hsa-let- CCTAGGAAGAGGTAGTAGGTTGCA 7 7d-prec TAGTTTTAGGGCAGGGATTTTGCC CACAAGGAGGTAACTATACGACCT GCTGCCTTTCTTAGG hsa-let- CTAGGAAGAGGTAGTAGTTTGCAT 8 7d-v1-prec AGTTTTAGGGCAAAGATTTTGCCC ACAAGTAGTTAGCTATACGACCTG CAGCCTTTTGTAG hsa-let- CTGGCTGAGGTAGTAGTTTGTGCT 9 7d-v2-prec GTTGGTCGGGTTGTGACATTGCCC GCTGTGGAGATAACTGCGCAAGCT ACTGCCTTGCTAG hsa-let- CCCGGGCTGAGGTAGGAGGTTGTA 10 7e-prec TAGTTGAGGAGGACACCCAAGGAG ATCACTATACGGCCTCCTAGCTTT CCCCAGG hsa-let- TCAGAGTGAGGTAGTAGATTGTAT 11 7f-1-prec AGTTGTGGGGTAGTGATTTTACCC TGTTCAGGAGATAACTATACAATC TATTGCCTTCCCTGA hsa-let- CTGTGGGATGAGGTAGTAGATTGT 12 7f-2-prec ATAGTTGTGGGGTAGTGATTTTAC CCTGTTCAGGAGATAACTATACAA TCTATTGCCTTCCCTGA hsa-let- CTGTGGGATGAGGTAGTAGATTGT 13 7f-2-prec ATAGTTTTAGGGTCATACCCCATC TTGGAGATAACTATACAGTCTACT GTCTTTCCCACGG hsa-let- TTGCCTGATTCCAGGCTGAGGTAG 14 7g-prec TAGTTTGTACAGTTTGAGGGTCTA TGATACCACCCGGTACAGGAGATA ACTGTACAGGCCACTGCCTTGCCA GGAACAGCGCGC hsa-let- CTGGCTGAGGTAGTAGTTTGTGCT 15 7i-prec GTTGGTCGGGTTGTGACATTGCCC GCTGTGGAGATAACTGCGCAAGCT ACTGCCTTGCTAG hsa-mir- ACCTACTCAGAGTACATACTTCTT 16 001b-1-prec TATGTACCCATATGAACATACAAT GCTATGGAATGTAAAGAAGTATGT ATTTTTGGTAGGC hsa-mir- CAGCTAACAACTTAGTAATACCTA 17 001b-1-prec CTCAGAGTACATACTTCTTTATGT ACCCATATGAACATACAATGCTAT GGAATGTAAAGAAGTATGTATTTT TGGTAGGCAATA hsa-mir- GCCTGCTTGGGAAACATACTTCTT 18 001b-2-prec TATATGCCCATATGGACCTGCTAA GCTATGGAATGTAAAGAAGTATGT ATCTCAGGCCGGG hsa-mir- TGGGAAACATACTTCTTTATATGC 19 001b-prec CCATATGGACCTGCTAAGCTATGG AATGTAAAGAAGTATGTATCTCA hsa-mir- ACCTACTCAGAGTACATACTTCTT 20 001d-prec TATGTACCCATATGAACATACAAT GCTATGGAATGTAAAGAAGTATGT ATTTTTGGTAGGC hsa-mir- TGGATGTTGGCCTAGTTCTGTGTG 21 007-1 GAAGACTAGTGATTTTGTTGTTTT TAGATAACTAAATCGACAACAAAT CACAGTCTGCCATATGGCACAGGC CATGCCTCTACA hsa-mir- TTGGATGTTGGCCTAGTTCTGTGT 22 007-1-prec GGAAGACTAGTGATTTTGTTGTTT TTAGATAACTAAATCGACAACAAA TCACAGTCTGCCATATGGCACAGG CCATGCCTCTACAG hsa-mir- CTGGATACAGAGTGGACCGGCTGG 23 007-2 CCCCATCTGGAAGACTAGTGATTT TGTTGTTGTCTTACTGCGCTCAAC AACAAATCCCAGTCTACCTAATGG TGCCAGCCATCGCA hsa-mir- CTGGATACAGAGTGGACCGGCTGG 24 007-2-prec CCCCATCTGGAAGACTAGTGATTT TGTTGTTGTCTTACTGCGCTCAAC AACAAATCCCAGTCTACCTAATGG TGCCAGCCATCGCA hsa-mir- AGATTAGAGTGGCTGTGGTCTAGT 25 007-3 GCTGTGTGGAAGACTAGTGATTTT GTTGTTCTGATGTACTACGACAAC AAGTCACAGCCGGCCTCATAGCGC AGACTCCCTTCGAC hsa-mir- AGATTAGAGTGGCTGTGGTCTAGT 26 007-3-prec GCTGTGTGGAAGACTAGTGATTTT GTTGTTCTGATGTACTACGACAAC AAGTCACAGCCGGCCTCATAGCGC AGACTCCCTTCGAC hsa-mir- CGGGGTTGGTTGTTATCTTTGGTT 27 009-1 ATCTAGCTGTATGAGTGGTGTGGA GTCTTCATAAAGCTAGATAACCGA AAGTAAAAATAACCCCA hsa-mir- GGAAGCGAGTTGTTATCTTTGGTT 28 009-2 ATCTAGCTGTATGAGTGTATTGGT CTTCATAAAGCTAGATAACCGAAA GTAAAAACTCCTTCA hsa-mir- GGAGGCCCGTTTCTCTCTTTGGTT 29 009-3 ATCTAGCTGTATGAGTGCCACAGA GCCGTCATAAAGCTAGATAACCGA AAGTAGAAATGATTCTCA hsa-mir- GATCTGTCTGTCTTCTGTATATAC 30 010a-prec CCTGTAGATCCGAATTTGTGTAAG GAATTTTGTGGTCACAAATTCGTA TCTAGGGGAATATGTAGTTGACAT AAACACTCCGCTCT hsa-mir- CCAGAGGTTGTAACGTTGTCTATA 31 010b-prec TATACCCTGTAGAACCGAATTTGT GTGGTATCCGTATAGTCACAGATT CGATTCTAGGGGAATATATGGTCG ATGCAAAAACTTCA hsa-mir- GCGCGAATGTGTGTTTAAAAAAAA 32 015a-2-prec TAAAACCTTGGAGTAAAGTAGCAG CACATAATGGTTTGTGGATTTTGA AAAGGTGCAGGCCATATTGTGCTG CCTCAAAAATAC hsa-mir- CCTTGGAGTAAAGTAGCAGCACAT 33 015a-prec AATGGTTTGTGGATTTTGAAAAGG TGCAGGCCATATTGTGCTGCCTCA AAAATACAAGG hsa-mir- CTGTAGCAGCACATCATGGTTTAC 34 015b-prec ATGCTACAGTCAAGATGCGAATCA TTATTTGCTGCTCTAG hsa-mir- TTGAGGCCTTAAAGTACTGTAGCA 35 015b-prec GCACATCATGGTTTACATGCTACA GTCAAGATGCGAATCATTATTTGC TGCTCTAGAAATTTAAGGAAATTC AT hsa-mir- GTCAGCAGTGCCTTAGCAGCACGT 36 016a-chr13 AAATATTGGCGTTAAGATTCTAAA ATTATCTCCAGTATTAACTGTGCT GCTGAAGTAAGGTTGAC hsa-mir- GTTCCACTCTAGCAGCACGTAAAT 37 016b-chr3 ATTGGCGTAGTGAAATATATATTA AACACCAATATTACTGTGCTGCTT TAGTGTGAC hsa-mir- GCAGTGCCTTAGCAGCACGTAAAT 38 016-prec-13 ATTGGCGTTAAGATTCTAAAATTA TCTCCAGTATTAACTGTGCTGCTG AAGTAAGGT hsa-mir- GTCAGAATAATGTCAAAGTGCTTA 39 017-prec CAGTGCAGGTAGTGATATGTGCAT CTACTGCAGTGAAGGCACTTGTAG CATTATGGTGAC hsa-mir- TGTTCTAAGGTGCATCTAGTGCAG 40 018-prec ATAGTGAAGTAGATTAGCATCTAC TGCCCTAAGTGCTCCTTCTGGCA hsa-mir- TTTTTGTTCTAAGGTGCATCTAGT 41 018-prec-13 GCAGATAGTGAAGTAGATTAGCAT CTACTGCCCTAAGTGCTCCTTCTG GCATAAGAA hsa-mir- GCAGTCCTCTGTTAGTTTTGCATA 42 019a-prec GTTGCACTACAAGAAGAATGTAGT TGTGCAAATCTATGCAAAACTGAT GGTGGCCTGC hsa-mir- CAGTCCTCTGTTAGTTTTGCATAG 43 019a-prec-13 TTGCACTACAAGAAGAATGTAGTT GTGCAAATCTATGCAAAACTGATG GTGGCCTG hsa-mir- CACTGTTCTATGGTTAGTTTTGCA 44 019b-1-prec GGTTTGCATCCAGCTGTGTGATAT TCTGCTGTGCAAATCCATGCAAAA CTGACTGTGGTAGTG hsa-mir- ACATTGCTACTTACAATTAGTTTT 45 019b-2-prec GCAGGTTTGCATTTCAGCGTATAT ATGTATATGTGGCTGTGCAAATCC ATGCAAAACTGATTGTGATAATGT hsa-mir- TTCTATGGTTAGTTTTGCAGGTTT 46 019b-prec-13 GCATCCAGCTGTGTGATATTCTGC TGTGCAAATCCATGCAAAACTGAC TGTGGTAG hsa-mir- TTACAATTAGTTTTGCAGGTTTGC 47 019b-prec-X ATTTCAGCGTATATATGTATATGT GGCTGTGCAAATCCATGCAAAACT GATTGTGAT hsa-mir- GTAGCACTAAAGTGCTTATAGTGC 48 020-prec AGGTAGTGTTTAGTTATCTACTGC ATTATGAGCACTTAAAGTACTGC hsa-mir- TGTCGGGTAGCTTATCAGACTGAT 49 021-prec GTTGACTGTTGAATCTCATGGCAA CACCAGTCGATGGGCTGTCTGACA hsa-mir- ACCTTGTCGGGTAGCTTATCAGAC 50 021-prec-17 TGATGTTGACTGTTGAATCTCATG GCAACACCAGTCGATGGGCTGTCT GACATTTTG hsa-mir- GGCTGAGCCGCAGTAGTTCTTCAG 51 022-prec TGGCAAGCTTTATGTCCTGACCCA GCTAAAGCTGCCAGTTGAAGAACT GTTGCCCTCTGCC hsa-mir- GGCCGGCTGGGGTTCCTGGGGATG 52 023a-prec GGATTTGCTTCCTGTCACAAATCA CATTGCCAGGGATTTCCAACCGAC C hsa-mir- CTCAGGTGCTCTGGCTGCTTGGGT 53 023b-prec TCCTGGCATGCTGATTTGTGACTT AAGATTAAAATCACATTGCCAGGG ATTACCACGCAACCACGACCTTGG C hsa-mir- CCACGGCCGGCTGGGGTTCCTGGG 54 023-prec-19 GATGGGATTTGCTTCCTGTCACAA ATCACATTGCCAGGGATTTCCAAC CGACCCTGA hsa-mir- CTCCGGTGCCTACTGAGCTGATAT 55 024-1-prec CAGTTCTCATTTTACACACTGGCT CAGTTCAGCAGGAACAGGAG hsa-mir- CTCTGCCTCCCGTGCCTACTGAGC 56 024-2-prec TGAAACACAGTTGGTTTGTGTACA CTGGCTCAGTTCAGCAGGAACAGG G hsa-mir- CCCTGGGCTCTGCCTCCCGTGCCT 57 024-prec-19 ACTGAGCTGAAACACAGTTGGTTT GTGTACACTGGCTCAGTTCAGCAG GAACAGGGG hsa-mir- CCCTCCGGTGCCTACTGAGCTGAT 58 024-prec-9 ATCAGTTCTCATTTTACACACTGG CTCAGTTCAGCAGGAACAGCATC hsa-mir- GGCCAGTGTTGAGAGGCGGAGACT 59 025-prec TGGGCAATTGCTGGACGCTGCCCT GGGCATTGCACTTGTCTCGGTCTG ACAGTGCCGGCC hsa-mir- AGGCCGTGGCCTCGTTCAAGTAAT 60 026a-prec CCAGGATAGGCTGTGCAGGTCCCA ATGGCCTATCTTGGTTACTTGCAC GGGGACGCGGGCCT hsa-mir- CCGGGACCCAGTTCAAGTAATTCA 61 026b-prec GGATAGGTTGTGTGCTGTCCAGCC TGTTCTCCATTACTTGGCTCGGGG ACCGG hsa-mir- CTGAGGAGCAGGGCTTAGCTGCTT 62 027a-prec GTGAGCAGGGTCCACACCAAGTCG TGTTCACAGTGGCTAAGTTCCGCC CCCCAG hsa-mir- AGGTGCAGAGCTTAGCTGATTGGT 63 027b-prec GAACAGTGATTGGTTTCCGCTTTG TTCACAGTGGCTAAGTTCTGCACC T hsa-mir- ACCTCTCTAACAAGGTGCAGAGCT 64 027b-prec TAGCTGATTGGTGAACAGTGATTG GTTTCCGCTTTGTTCACAGTGGCT AAGTTCTGCACCTGAAGAGAAGGT G hsa-mir- CCTGAGGAGCAGGGCTTAGCTGCT 65 027-prec-19 TGTGAGCAGGGTCCACACCAAGTC GTGTTCACAGTGGCTAAGTTCCGC CCCCCAGG hsa-mir- GGTCCTTGCCCTCAAGGAGCTCAC 66 028-prec AGTCTATTGAGTTACCTTTCTGAC TTTCCCACTAGATTGTGAGCTCCT GGAGGGCAGGCACT hsa-mir- CCTTCTGTGACCCCTTAGAGGATG 67 029a-2 ACTGATTTCTTTTGGTGTTCAGAG TCAATATAATTTTCTAGCACCATC TGAAATCGGTTATAATGATTGGGG AAGAGCACCATG hsa-mir- ATGACTGATTTCTTTTGGTGTTCA 68 029a-prec GAGTCAATATAATTTTCTAGCACC ATCTGAAATCGGTTAT hsa-mir- ACCACTGGCCCATCTCTTACACAG 69 029c-prec GCTGACCGATTTCTCCTGGTGTTC AGAGTCTGTTTTTGTCTAGCACCA TTTGAAATCGGTTATGATGTAGGG GGAAAAGCAGCAGC hsa-mir- GCGACTGTAAACATCCTCGACTGG 70 030a-prec AAGCTGTGAAGCCACAGATGGGCT TTCAGTCGGATGTTTGCAGCTGC hsa-mir- ATGTAAACATCCTACACTCAGCTG 71 030b-prec TAATACATGGATTGGCTGGGAGGT GGATGTTTACGT hsa-mir- ACCAAGTTTCAGTTCATGTAAACA 72 030b-prec TCCTACACTCAGCTGTAATACATG GATTGGCTGGGAGGTGGATGTTTA CTTCAGCTGACTTGGA hsa-mir- AGATACTGTAAACATCCTACACTC 73 030c-prec TCAGCTGTGGAAAGTAAGAAAGCT GGGAGAAGGCTGTTTACTCTTTCT hsa-mir- GTTGTTGTAAACATCCCCGACTGG 74 030d-prec AAGCTGTAAGACACAGCTAAGCTT TCAGTCAGATGTTTGCTGCTAC hsa-mir- GGAGAGGAGGCAAGATGCTGGCAT 75 031-prec AGCTGTTGAACTGGGAACCTGCTA TGCCAACATATTGCCATCTTTCC hsa-mir- GGAGATATTGCACATTACTAAGTT 76 032-prec GCATGTTGTCACGGCCTCAATGCA ATTTAGTGTGTGTGATATTTTC hsa-mir- GGGGGCCGAGAGAGGCGGGCGGCC 77 033b-prec CCGCGGTGCATTGCTGTTGCATTG CACGTGTGTGAGGCGGGTGCAGTG CCTCGGCAGTGCAGCCCGGAGCCG GCCCCTGGCACCAC hsa-mir- CTGTGGTGCATTGTAGTTGCATTG 78 033-prec CATGTTCTGGTGGTACCCATGCAA TGTTTCCACAGTGCATCACAG hsa-mir- GGCCAGCTGTGAGTGTTTCTTTGG 79 034-prec CAGTGTCTTAGCTGGTTGTTGTGA GCAATAGTAAGGAAGCAATCAGCA AGTATACTGCCCTAGAAGTGCTGC ACGTTGTGGGGCCC hsa-mir- TCAGAATAATGTCAAAGTGCTTAC 80 091-prec-13 AGTGCAGGTAGTGATATGTGCATC TACTGCAGTGAAGGCACTTGTAGC ATTATGGTGA hsa-mir- CTTTCTACACAGGTTGGGATCGGT 81 092-prec-13 = TGCAATGCTGTGTTTCTGTATGGT 092-1 ATTGCACTTGTCCCGGCCTGTTGA GTTTGG hsa-mir- TCATCCCTGGGTGGGGATTTGTTG 82 092-prec-X = CATTACTTGTGTTCTATATAAAGT 092-2 ATTGCACTTGTCCCGGCCTGTGGA AGA hsa-mir- CTGGGGGCTCCAAAGTGCTGTTCG 83 093-prec-7.1 = TGCAGGTAGTGTGATTACCCAACC 093-1 TACTGCTGAGCTAGCACTTCCCGA GCCCCCGG hsa-mir- CTGGGGGCTCCAAAGTGCTGTTCG 84 093-prec-7.2 = TGCAGGTAGTGTGATTACCCAACC 093-2 TACTGCTGAGCTAGCACTTCCCGA GCCCCCGG hsa-mir- AACACAGTGGGCACTCAATAAATG 85 095-prec-4 TCTGTTGAATTGAAATGCGTTACA TTCAACGGGTATTTATTGAGCACC CACTCTGTG hsa-mir- TGGCCGATTTTGGCACTAGCACAT 86 096-prec-7 TTTTGCTTGTGTCTCTCCGCTCTG AGCAATCATGTGCAGTGCCAATAT GGGAAA hsa-mir- GTGAGGTAGTAAGTTGTATTGTTG 87 098-prec-X TGGGGTAGGGATATTAGGCCCCAA TTAGAAGATAACTATACAACTTAC TACTTTCC hsa-mir- GGCACCCACCCGTAGAACCGACCT 88 099b-prec-19 TGCGGGGCCTTCGCCGCACACAAG CTCGTGTCTGTGGGTCCGTGTC hsa-mir- CCCATTGGCATAAACCCGTAGATC 89 099-prec-21 CGATCTTGTGGTGAAGTGGACCGC ACAAGCTCGCTTCTATGGGTCTGT GTCAGTGTG hsa-mir- AAGAGAGAAGATATTGAGGCCTGT 90 100-1/2-prec TGCCACAAACCCGTAGATCCGAAC TTGTGGTATTAGTCCGCACAAGCT TGTATCTATAGGTATGTGTCTGTT AGGCAATCTCAC hsa-mir- CCTGTTGCCACAAACCCGTAGATC 91 100-prec-11 CGAACTTGTGGTATTAGTCCGCAC AAGCTTGTATCTATAGGTATGTGT CTGTTAGG hsa-mir- AGGCTGCCCTGGCTCAGTTATCAC 92 101-1/2-prec AGTGCTGATGCTGTCTATTCTAAA GGTACAGTACTGTGATAACTGAAG GATGGCAGCCATCTTACCTTCCAT CAGAGGAGCCTCAC hsa-mir- TCAGTTATCACAGTGCTGATGCTG 93 101-prec TCCATTCTAAAGGTACAGTACTGT GATAACTGA hsa-mir- TGCCCTGGCTCAGTTATCACAGTG 94 101-prec-1 CTGATGCTGTCTATTCTAAAGGTA CAGTACTGTGATAACTGAAGGATG GCA hsa-mir- TGTCCTTTTTCGGTTATCATGGTA 95 101-prec-9 CCGATGCTGTATATCTGAAAGGTA CAGTACTGTGATAACTGAAGAATG GTG hsa-mir- CTTCTGGAAGCTGGTTTCACATGG 96 102-prec-1 TGGCTTAGATTTTTCCATCTTTGT ATCTAGCACCATTTGAAATCAGTG TTTTAGGAG hsa-mir- CTTCAGGAAGCTGGTTTCATATGG 97 102-prec-7.1 TGGTTTAGATTTAAATAGTGATTG TCTAGCACCATTTGAAATCAGTGT TCTTGGGGG hsa-mir- CTTCAGGAAGCTGGTTTCATATGG 98 102-prec-7.2 TGGTTTAGATTTAAATAGTGATTG TCTAGCACCATTTGAAATCAGTGT TCTTGGGGG hsa-mir- TTGTGCTTTCAGCTTCTTTACAGT 99 103-2-prec GCTGCCTTGTAGCATTCAGGTCAA GCAACATTGTACAGGGCTATGAAA GAACCA hsa-mir- TTGTGCTTTCAGCTTCTTTACAGT 100 103-prec-20 GCTGCCTTGTAGCATTCAGGTCAA GCAACATTGTACAGGGCTATGAAA GAACCA hsa-mir- TACTGCCCTCGGCTTCTTTACAGT 101 103-prec-5 = GCTGCCTTGTTGCATATGGATCAA 103-1 GCAGCATTGTACAGGGCTATGAAG GCATTG hsa-mir- AAATGTCAGACAGCCCATCGACTG 102 104-prec-17 GTGTTGCCATGAGATTCAACAGTC AACATCAGTCTGATAAGCTACCCG ACAAGG hsa-mir- TGTGCATCGTGGTCAAATGCTCAG 103 105-prec-X.1 = ACTCCTGTGGTGGCTGCTCATGCA 105-1 CCACGGATGTTTGAGCATGTGCTA CGGTGTCTA hsa-mir- TGTGCATCGTGGTCAAATGCTCAG 104 105-prec-X.2 = ACTCCTGTGGTGGCTGCTCATGCA 105-2 CCACGGATGTTTGAGCATGTGCTA CGGTGTCTA hsa-mir- CCTTGGCCATGTAAAAGTGCTTAC 105 106-prec-X AGTGCAGGTAGCTTTTTGAGATCT ACTGCAATGTAAGCACTTCTTACA TTACCATGG hsa-mir- CTCTCTGCTTTCAGCTTCTTTACA 106 107-prec-10 GTGTTGCCTTGTGGCATGGAGTTC AAGCAGCATTGTACAGGGCTATCA AAGCACAGA hsa-mir- CCTTAGCAGAGCTGTGGAGTGTGA 107 122a-prec CAATGGTGTTTGTGTCTAAACTAT CAAACGCCATTATCACACTAAATA GCTACTGCTAGGC hsa-mir- AGCTGTGGAGTGTGACAATGGTGT 108 122a-prec TTGTGTCCAAACTATCAAACGCCA TTATCACACTAAATAGCT hsa-mir- ACATTATTACTTTTGGTACGCGCT 109 123-prec GTGACACTTCAAACTCGTACCGTG AGTAATAATGCGC hsa-mir- tccttcctCAGGAGAAAGGCCTCT 110 124a-1-prec CTCTCCGTGTTCACAGCGGACCTT GATTTAAATGTCCATACAATTAAG GCACGCGGTGAATGCCAAGAATGG GGCT hsa-mir- AGGCCTCTCTCTCCGTGTTCACAG 111 124a-1-prec CGGACCTTGATTTAAATGTCCATA CAATTAAGGCACGCGGTGAATGCC AAGAATGGGGCTG hsa-mir- ATCAAGATTAGAGGCTCTGCTCTC 112 124a-2-prec CGTGTTCACAGCGGACCTTGATTT AATGTCATACAATTAAGGCACGCG GTGAATGCCAAGAGCGGAGCCTAC GGCTGCACTTGAAG hsa-mir- CCCGCCCCAGCCCTGAGGGCCCCT 113 124a-3-prec CTGCGTGTTCACAGCGGACCTTGA TTTAATGTCTATACAATTAAGGCA CGCGGTGAATGCCAAGAGAGGCGC CTCCGCCGCTCCTT hsa-mir- TGAGGGCCCCTCTGCGTGTTCACA 114 124a-3-prec GCGGACCTTGATTTAATGTCTATA CAATTAAGGCACGCGGTGAATGCC AAGAGAGGCGCCTCC hsa-mir- CTCTGCGTGTTCACAGCGGACCTT 115 124a-prec GATTTAATGTCTATACAATTAAGG CACGCGGTGAATGCCAAGAG hsa-mir- CTCTCCGTGTTCACAGCGGACCTT 116 124b-prec GATTTAATGTCATACAATTAAGGC ACGCGGTGAATGCCAAGAG hsa-mir- TGCCAGTCTCTAGGTCCCTGAGAC 117 125a-prec CCTTTAACCTGTGAGGACATCCAG GGTCACAGGTGAGGTTCTTGGGAG CCTGGCGTCTGGCC hsa-mir- GGTCCCTGAGACCCTTTAACCTGT 118 125a-prec GAGGACATCCAGGGTCACAGGTGA GGTTCTTGGGAGCCTGG hsa-mir- ACATTGTTGCGCTCCTCTCAGTCC 119 125b-1 CTGAGACCCTAACTTGTGATGTTT ACCGTTTAAATCCACGGGTTAGGC TCTTGGGAGCTGCGAGTCGTGCTT TTGCATCCTGGA hsa-mir- TGCGCTCCTCTCAGTCCCTGAGAC 120 125b-1 CCTAACTTGTGATGTTTACCGTTT AAATCCACGGGTTAGGCTCTTGGG AGCTGCGAGTCGTGCT hsa-mir- ACCAGACTTTTCCTAGTCCCTGAG 121 125b-2-prec ACCCTAACTTGTGAGGTATTTTAG TAACATCACAAGTCAGGCTCTTGG GACCTAGGCGGAGGGGA hsa-mir- CCTAGTCCCTGAGACCCTAACTTG 122 125b-2-prec TGAGGTATTTTAGTAACATCACAA GTCAGGCTCTTGGGACCTAGGC hsa-mir- CGCTGGCGACGGGACATTATTACT 123 126-prec TTTGGTACGCGCTGTGACACTTCA AACTCGTACCGTGAGTAATAATGC GCCGTCCACGGCA hsa-mir- ACATTATTACTTTTGGTACGCGCT 124 126-prec GTGACACTTCAAACTCGTACCGTG AGTAATAATGCGC hsa-mir- TGTGATCACTGTCTCCAGCCTGCT 125 127-prec GAAGCTCAGAGGGCTCTGATTCAG AAAGATCATCGGATCCGTCTGAGC TTGGCTGGTCGGAAGTCTCATCAT C hsa-mir- CCAGCCTGCTGAAGCTCAGAGGGC 126 127-prec TCTGATTCAGAAAGATCATCGGAT CCGTCTGAGCTTGGCTGGTCGG hsa-mir- TGAGCTGTTGGATTCGGGGCCGTA 127 128a-prec GCACTGTCTGAGAGGTTTACATTT CTCACAGTGAACCGGTCTCTTTTT CAGCTGCTTC hsa-mir- GCCCGGCAGCCACTGTGCAGTGGG 128 128b-prec AAGGGGGGCCGATACACTGTACGA GAGTGAGTAGCAGGTCTCACAGTG AACCGGTCTCTTTCCCTACTGTGT CACACTCCTAATGG hsa-mir- GTTGGATTCGGGGCCGTAGCACTG 129 128-prec TCTGAGAGGTTTACATTTCTCACA GTGAACCGGTCTCTTTTTCAGC hsa-mir- TGGATCTTTTTGCGGTCTGGGCTT 130 129-prec GCTGTTCCTCTCAACAGTAGTCAG GAAGCCCTTACCCCAAAAAGTATC TA hsa-mir- TGCTGCTGGCCAGAGCTCTTTTCA 131 130a-prec CATTGTGCTACTGTCTGCACCTGT CACTAGCAGTGCAATGTTAAAAGG GCATTGGCCGTGTAGTG hsa-mir- gccaggaggcggGGTTGGTTGTTA 132 131-1-prec TCTTTGGTTATCTAGCTGTATGAG TGGTGTGGAGTCTTCATAAAGCTA GATAACCGAAAGTAAAAATAACCC CATACACTGCGCAG hsa-mir- CACGGCGCGGCAGCGGCACTGGCT 133 131-3-prec AAGGGAGGCCCGTTTCTCTCTTTG GTTATCTAGCTGTATGAGTGCCAC AGAGCCGTCATAAAGCTAGATAAC CGAAAGTAGAAATG hsa-mir- GTTGTTATCTTTGGTTATCTAGCT 134 131-prec GTATGAGTGTATTGGTCTTCATAA AGCTAGATAACCGAAAGTAAAAAC hsa-mir- CCGCCCCCGCGTCTCCAGGGCAAC 135 132-prec CGTGGCTTTCGATTGTTACTGTGG GAACTGGAGGTAACAGTCTACAGC CATGGTCGCCCCGCAGCACGCCCA CGCGC hsa-mir- GGGCAACCGTGGCTTTCGATTGTT 136 132-prec ACTGTGGGAACTGGAGGTAACAGT CTACAGCCATGGTCGCCC hsa-mir- ACAATGCTTTGCTAGAGCTGGTAA 137 133a-1 AATGGAACCAAATCGCCTCTTCAA TGGATTTGGTCCCCTTCAACCAGC TGTAGCTATGCATTGA hsa-mir- GGGAGCCAAATGCTTTGCTAGAGC 138 133a-2 TGGTAAAATGGAACCAAATCGACT GTCCAATGGATTTGGTCCCCTTCA ACCAGCTGTAGCTGTGCATTGATG GCGCCG hsa-mir- GCTAGAGCTGGTAAAATGGAACCA 139 133-prec AATCGCCTCTTCAATGGATTTGGT CCCCTTCAACCAGCTGTAGC hsa-mir- CAGGGTGTGTGACTGGTTGACCAG 140 134-prec AGGGGCATGCACTGTGTTCACCCT GTGGGCCACCTAGTCACCAACCCT C hsa-mir- AGGGTGTGTGACTGGTTGACCAGA 141 134-prec GGGGCATGCACTGTGTTCACCCTG TGGGCCACCTAGTCACCAACCCT hsa-mir- AGGCCTCGCTGTTCTCTATGGCTT 142 135-1-prec TTTATTCCTATGTGATTCTACTGC TCACTCATATAGGGATTGGAGCCG TGGCGCACGGCGGGGACA hsa-mir- AGATAAATTCACTCTAGTGCTTTA 143 135-2-prec TGGCTTTTTATTCCTATGTGATAG TAATAAAGTCTCATGTAGGGATGG AAGCCATGAAATACATTGTGAAAA ATCA hsa-mir- CTATGGCTTTTTATTCCTATGTGA 144 135-prec TTCTACTGCTCACTCATATAGGGA TTGGAGCCGTGG hsa-mir- TGAGCCCTCGGAGGACTCCATTTG 145 136-prec TTTTGATGATGGATTCTTATGCTC CATCATCGTCTCAAATGAGTCTTC AGAGGGTTCT hsa-mir- GAGGACTCCATTTGTTTTGATGAT 146 136-prec GGATTCTTATGCTCCATCATCGTC TCAAATGAGTCTTC hsa-mir- CTTCGGTGACGGGTATTCTTGGGT 147 137-prec GGATAATACGGATTACGTTGTTAT TGCTTAAGAATACGCGTAGTCGAG G hsa-mir- CCCTGGCATGGTGTGGTGGGGCAG 148 138-1-prec CTGGTGTTGTGAATCAGGCCGTTG CCAATCAGAGAACGGCTACTTCAC AACACCAGGGCCACACCACACTAC AGG hsa-mir- CGTTGCTGCAGCTGGTGTTGTGAA 149 138-2-prec TCAGGCCGACGAGCAGCGCATCCT CTTACCCGGCTATTTCACGACACC AGGGTTGCATCA hsa-mir- CAGCTGGTGTTGTGAATCAGGCCG 150 138-prec ACGAGCAGCGCATCCTCTTACCCG GCTATTTCACGACACCAGGGTTG hsa-mir- GTGTATTCTACAGTGCACGTGTCT 151 139-prec CCAGTGTGGCTCGGAGGCTGGAGA CGCGGCCCTGTTGGAGTAAC hsa-mir- TGTGTCTCTCTCTGTGTCCTGCCA 152 140 GTGGTTTTACCCTATGGTAGGTTA CGTCATGCTGTTCTACCACAGGGT AGAACCACGGACAGGATACCGGGG CACC hsa-mir- TCCTGCCAGTGGTTTTACCCTATG 153 140as-prec GTAGGTTACGTCATGCTGTTCTAC CACAGGGTAGAACCACGGACAGGA hsa-mir- CCTGCCAGTGGTTTTACCCTATGG 154 140s-prec TAGGTTACGTCATGCTGTTCTACC ACAGGGTAGAACCACGGACAGG hsa-mir- CGGCCGGCCCTGGGTCCATCTTCC 155 141-prec AGTACAGTGTTGGATGGTCTAATT GTGAAGCTCCTAACACTGTCTGGT AAAGATGGCTCCCGGGTGGGTTC hsa-mir- GGGTCCATCTTCCAGTACAGTGTT 156 141-prec GGATGGTCTAATTGTGAAGCTCCT AACACTGTCTGGTAAAGATGGCCC hsa-mir- ACCCATAAAGTAGAAAGCACTACT 157 142as-prec AACAGCACTGGAGGGTGTAGTGTT TCCTACTTTATGGATG hsa-mir- GACAGTGCAGTCACCCATAAAGTA 158 142-prec GAAAGCACTACTAACAGCACTGGA GGGTGTAGTGTTTCCTACTTTATG GATGAGTGTACTGTG hsa-mir- ACCCATAAAGTAGAAAGCACTACT 159 142s-pres AACAGCACTGGAGGGTGTAGTGTT TCCTACTTTATGGATG hsa-mir- GCGCAGCGCCCTGTCTCCCAGCCT 160 143-prec GAGGTGCAGTGCTGCATCTCTGGT CAGTTGGGAGTCTGAGATGAAGCA CTGTAGCTCAGGAAGAGAGAAGTT GTTCTGCAGC hsa-mir- CCTGAGGTGCAGTGCTGCATCTCT 161 143-prec GGTCAGTTGGGAGTCTGAGATGAA GCACTGTAGCTCAGG hsa-mir- TGGGGCCCTGGCTGGGATATCATC 162 144-prec ATATACTGTAAGTTTGCGATGAGA CACTACAGTATAGATGATGTACTA GTCCGGGCACCCCC hsa-mir- GGCTGGGATATCATCATATACTGT 163 144-prec AAGTTTGCGATGAGACACTACAGT ATAGATGATGTACTAGTC hsa-mir- CACCTTGTCCTCACGGTCCAGTTT 164 145-prec TCCCAGGAATCCCTTAGATGCTAA GATGGGGATTCCTGGAAATACTGT TCTTGAGGTCATGGTT hsa-mir- CTCACGGTCCAGTTTTCCCAGGAA 165 145-prec TCCCTTAGATGCTAAGATGGGGAT TCCTGGAAATACTGTTCTTGAG hsa-mir- CCGATGTGTATCCTCAGCTTTGAG 166 146-prec AACTGAATTCCATGGGTTGTGTCA GTGTCAGACCTCTGAAATTCAGTT CTTCAGCTGGGATATCTCTGTCAT CGT hsa-mir- AGCTTTGAGAACTGAATTCCATGG 167 146-prec GTTGTGTCAGTGTCAGACCTGTGA AATTCAGTTCTTCAGCT hsa-mir- AATCTAAAGACAACATTTCTGCAC 168 147-prec ACACACCAGACTATGGAAGCCAGT GTGTGGAAATGCTTCTGCTAGATT hsa-mir- GAGGCAAAGTTCTGAGACACTCCG 169 148-prec ACTCTGAGTATGATAGAAGTCAGT GCACTACAGAACTTTGTCTC hsa-mir- GCCGGCGCCCGAGCTCTGGCTCCG 170 149-prec TGTCTTCACTCCCGTGCTTGTCCG AGGAGGGAGGGAGGGACGGGGGCT GTGCTGGGGCAGCTGGA hsa-mir- GCTCTGGCTCCGTGTCTTCACTCC 171 149-prec CGTGCTTGTCCGAGGAGGGAGGGA GGGAC hsa-mir- CTCCCCATGGCCCTGTCTCCCAAC 172 150-prec CCTTGTACCAGTGCTGGGCTCAGA CCCTGGTACAGGCCTGGGGGACAG GGACCTGGGGAC hsa-mir- CCCTGTCTCCCAACCCTTGTACCA 173 150-prec GTGCTGGGCTCAGACCCTGGTACA GGCCTGGGGGACAGGG hsa-mir- CCTGCCCTCGAGGAGCTCACAGTC 174 151-prec TAGTATGTCTCATCCCCTACTAGA CTGAAGCTCCTTGAGGACAGG hsa-mir- TGTCCCCCCCGGCCCAGGTTCTGT 175 152-prec GATACACTCCGACTCGGGCTCTGG AGCAGTCAGTGCATGACAGAACTT GGGCCCGGAAGGACC hsa-mir- GGCCCAGGTTCTGTGATACACTCC 176 152-prec GACTCGGGCTCTGGAGCAGTCAGT GCATGACAGAACTTGGGCCCCGG hsa-mir- CTCACAGCTGCCAGTGTCATTTTT 177 153-1-prec GTGATCTGCAGCTAGTATTCTCAC TCCAGTTGCATAGTCACAAAAGTG ATCATTGGCAGGTGTGGC hsa-mir- tctctctctccctcACAGCTGCCA 178 153-1-prec GTGTCATTGTCACAAAAGTGATCA TTGGCAGGTGTGGCTGCTGCATG hsa-mir- AGCGGTGGCCAGTGTCATTTTTGT 179 153-2-prec GATGTTGCAGCTAGTAATATGAGC CCAGTTGCATAGTCACAAAAGTGA TCATTGGAAACTGTG hsa-mir- CAGTGTCATTTTTGTGATGTTGCA 180 153-2-prec GCTAGTAATATGAGCCCAGTTGCA TAGTCACAAAAGTGATCATTG hsa-mir- GTGGTACTTGAAGATAGGTTATCC 181 154-prec GTGTTGCCTTCGCTTTATTTGTGA CGAATCATACACGGTTGACCTATT TTTCAGTACCAA hsa-mir- GAAGATAGGTTATCCGTGTTGCCT 182 154-prec TCGCTTTATTTGTGACGAATCATA CACGGTTGACCTATTTTT hsa-mir- CTGTTAATGCTAATCGTGATAGGG 183 155-prec GTTTTTGCCTCCAACTGACTCCTA CATATTAGCATTAACAG hsa-mir- CAATGTCAGCAGTGCCTTAGCAGC 184 16-2-prec ACGTAAATATTGGCGTTAAGATTC TAAAATTATCTCCAGTATTAACTG TGCTGCTGAAGTAAGGTTGACCAT ACTCTACAGTTG hsa-mir- AGAAGGGCTATCAGGCCAGCCTTC 185 181a-prec AGAGGACTCCAAGGAACATTCAAC GCTGTCGGTGAGTTTGGGATTTGA AAAAACCACTGACCGTTGACTGTA CCTTGGGGTCCTTA hsa-mir- TGAGTTTTGAGGTTGCTTCAGTGA 186 181b-prec ACATTCAACGCTGTCGGTGAGTTT GGAATTAAAATCAAAACCATCGAC CGTTGATTGTACCCTATGGCTAAC CATCATCTACTCCA hsa-mir- CGGAAAATTTGCCAAGGGTTTGGG 187 181c-prec GGAACATTCAACCTGTCGGTGAGT TTGGGCAGCTCAGGCAAACCATCG ACCGTTGAGTGGACCCTGAGGCCT GGAATTGCCATCCT hsa-mir- GAGCTGCTTGCCTCCCCCCGTTTT 188 182-as-prec TGGCAATGGTAGAACTCACACTGG TGAGGTAACAGGATCCGGTGGTTC TAGACTTGCCAACTATGGGGCGAG GACTCAGCCGGCAC hsa-mir- TTTTTGGCAATGGTAGAACTCACA 189 182-prec CTGGTGAGGTAACAGGATCCGGTG GTTCTAGACTTGCCAACTATGG hsa-mir- CCGCAGAGTGTGACTCCTGTTCTG 190 183-prec TGTATGGCACTGGTAGAATTCACT GTGAACAGTCTCAGTCAGTGAATT ACCGAAGGGCCATAAACAGAGCAG AGACAGATCCACGA hsa-mir- CCAGTCACGTCCCCTTATCACTTT 191 184-prec TCCAGCCCAGCTTTGTGACTGTAA GTGTTGGACGGAGAACTGATAAGG GTAGGTGATTGA hsa-mir- CCTTATCACTTTTCCAGCCCAGCT 192 184-prec TTGTGACTGTAAGTGTTGGACGGA GAACTGATAAGGGTAGG hsa-mir- AGGGGGCGAGGGATTGGAGAGAAA 193 185-prec GGCAGTTCCTGATGGTCCCCTCCC CAGGGGCTGGCTTTCCTCTGGTCC TTCCCTCCCA hsa-mir- AGGGATTGGAGAGAAAGGCAGTTC 194 185-prec CTGATGGTCCCCTCCCCAGGGGCT GGCTTTCCTCTGGTCCTT hsa-mir- TGCTTGTAACTTTCCAAAGAATTC 195 186-prec TCCTTTTGGGCTTTCTGGTTTTAT TTTAAGCCCAAAGGTGAATTTTTT GGGAAGTTTGAGCT hsa-mir- ACTTTCCAAAGAATTCTCCTTTTG 196 186-prec GGCTTTCTGGTTTTATTTTAAGCC CAAAGGTGAATTTTTTGGGAAGT hsa-mir- GGTCGGGCTCACCATGACACAGTG 197 187-prec TGAGACTCGGGCTACAACACAGGA CCCGGGGCGCTGCTCTGACCCCTC GTGTCTTGTGTTGCAGCCGGAGGG ACGCAGGTCCGCA hsa-mir- TGCTCCCTCTCTCACATCCCTTGC 198 188-prec ATGGTGGAGGGTGAGCTTTCTGAA AACCCCTCCCACATGCAGGGTTTG CAGGATGGCGAGCC hsa-mir- TCTCACATCCCTTGCATGGTGGAG 199 188-prec GGTGAGCTTTCTGAAAACCCCTCC CACATGCAGGGTTTGCAGGA hsa-mir- CTGTCGATTGGACCCGCCCTCCGG 200 189-prec TGCCTACTGAGCTGATATCAGTTC TCATTTTACACACTGGCTCAGTTC AGCAGGAACAGGAGTCGAGCCCTT GAGCAA hsa-mir- CTCCGGTGCCTACTGAGCTGATAT 201 189-prec CAGTTCTCATTTTACACACTGGCT CAGTTCAGCAGGAACAGGAG hsa-mir- TGCAGGCCTCTGTGTGATATGTTT 202 190-prec GATATATTAGGTTGTTATTTAATC CAACTATATATCAAACATATTCCT ACAGTGTCTTGCC hsa-mir- CTGTGTGATATGTTTGATATATTA 203 190-prec GGTTGTTATTTAATCCAACTATAT ATCAAACATATTCCTACAG hsa-mir- CGGCTGGACAGCGGGCAACGGAAT 204 191-prec CCCAAAAGCAGCTGTTGTCTCCAG AGCATTCCAGCTGCGCTTGGATTT CGTCCCCTGCTCTCCTGCCT hsa-mir- AGCGGGCAACGGAATCCCAAAAGC 205 191-prec AGCTGTTGTCTCCAGAGCATTCCA GCTGCGCTTGGATTTCGTCCCCTG CT hsa-mir- CCGAGACCGAGTGCACAGGGCTCT 206 192-2/3 GACCTATGAATTGACAGCCAGTGC TCTCGTCTCCCCTCTGGCTGCCAA TTCCATAGGTCACAGGTATGTTCG CCTCAATGCCAG hsa-mir- GCCGAGACCGAGTGCACAGGGCTC 207 192-prec TGACCTATGAATTGACAGCCAGTG CTCTCGTCTCCCCTCTGGCTGCCA ATTCCATAGGTCACAGGTATGTTC GCCTCAATGCCAGC hsa-mir- CGAGGATGGGAGCTGAGGGCTGGG 208 193-prec TCTTTGCGGGCGAGATGAGGGTGT CGGATCAACTGGCCTACAAAGTCC CAGTTCTCGGCCCCCG hsa-mir- GCTGGGTCTTTGCGGGCGAGATGA 209 193-prec GGGTGTCGGATCAACTGGCCTACA AAGTCCCAGT hsa-mir- ATGGTGTTATCAAGTGTAACAGCA 210 194-prec ACTCCATGTGGACTGTGTACCAAT TTCCAGTGGAGATGCTGTTACTTT TGATGGTTACCAA hsa-mir- GTGTAACAGCAACTCCATGTGGAC 211 194-prec TGTGTACCAATTTCCAGTGGAGAT GCTGTTACTTTTGAT hsa-mir- AGCTTCCCTGGCTCTAGCAGCACA 212 195-prec GAAATATTGGCACAGGGAAGCGAG TCTGCCAATATTGGCTGTGCTGCT CCAGGCAGGGTGGTG hsa-mir- TAGCAGCACAGAAATATTGGCACA 213 195-prec GGGAAGCGAGTCTGCCAATATTGG CTGTGCTGCT hsa-mir- CTAGAGCTTGAATTGGAACTGCTG 214 196-1-prec AGTGAATTAGGTAGTTTCATGTTG TTGGGCCTGGGTTTCTGAACACAA CAACATTAAACCACCCGATTCACG GCAGTTACTGCTCC hsa-mir- GTGAATTAGGTAGTTTCATGTTGT 215 196-1-prec TGGGCCTGGGTTTCTGAACACAAC AACATTAAACCACCCGATTCAC hsa-mir- TGCTCGCTCAGCTGATCTGTGGCT 216 196-2-prec TAGGTAGTTTCATGTTGTTGGGAT TGAGTTTTGAACTCGGCAACAAGA AACTGCCTGAGTTACATCAGTCGG TTTTCGTCGAGGGC hsa-mir- GTGAATTAGGTAGTTTCATGTTGT 217 196-prec TGGGCCTGGGTTTCTGAACACAAC AACATTAAACCACCCGATTCAC hsa-mir- GGCTGTGCCGGGTAGAGAGGGCAG 218 197-prec TGGGAGGTAAGAGCTCTTCACCCT TCACCACCTTCTCCACCCAGCATG GCC hsa-mir- TCATTGGTCCAGAGGGGAGATAGG 219 198-prec TTCCTGTGATTTTTCCTTCTTCTC TATAGAATAAATGA hsa-mir- GCCAACCCAGTGTTCAGACTACCT 220 199a-1-prec GTTCAGGAGGCTCTCAATGTGTAC AGTAGTCTGCACATTGGTTAGGC hsa-mir- AGGAAGCTTCTGGAGATCCTGCTC 221 199a-2-prec CGTCGCCCCAGTGTTCAGACTACC TGTTCAGGACAATGCCGTTGTACA GTAGTCTGCACATTGGTTAGACTG GGCAAGGGAGAGCA hsa-mir- CCAGAGGACACCTCCACTCCGTCT 222 199b-prec ACCCAGTGTTTAGACTATCTGTTC AGGACTCCCAAATTGTACAGTAGT CTGCACATTGGTTAGGCTGGGCTG GGTTAGACCCTCGG hsa-mir- GCCAACCCAGTGTTCAGACTACCT 223 199s-prec GTTCAGGAGGCTCTCAATGTGTAC AGTAGTCTGCACATTGGTTAGGC hsa-mir- GCCGTGGCCATCTTACTGGGCAGC 224 200a-prec ATTGGATGGAGTCAGGTCTCTAAT ACTGCCTGGTAATGATGACGGC hsa-mir- CCAGCTCGGGCAGCCGTGGCCATC 225 200b-prec TTACTGGGCAGCATTGGATGGAGT CAGGTCTCTAATACTGCCTGGTAA TGATGACGGCGGAGCCCTGCACG hsa-mir- GTTCCTTTTTCCTATGCATATACT 226 202-prec TCTTTGAGGATCTGGCCTAAAGAG GTATAGGGCATGGGAAGATGGAGC hsa-mir- GTGTTGGGGACTCGCGCGCTGGGT 227 203-prec CCAGTGGTTCTTAACAGTTCAACA GTTCTGTAGCGCAATTGTGAAATG TTTAGGACCACTAGACCCGGCGGG CGCGGCGACAGCGA hsa-mir- GGCTACAGTCTTTCTTCATGTGAC 228 204-prec TCGTGGACTTCCCTTTGTCATCCT ATGCCTGAGAATATATGAAGGAGG CTGGGAAGGCAAAGGGACGTTCAA TTGTCATCACTGGC hsa-mir- AAAGATCCTCAGACAATCCATGTG 229 205-prec CTTCTCTTGTCCTTCATTCCACCG GAGTCTGTCTCATACCCAACCAGA TTTCAGTGGAGTGAAGTTCAGGAG GCATGGAGCTGACA hsa-mir- TGCTTCCCGAGGCCACATGCTTCT 230 206-prec TTATATCCCCATATGGATTACTTT GCTATGGAATGTAAGGAAGTGTGT GGTTTCGGCAAGTG hsa-mir- AGGCCACATGCTTCTTTATATCCC 231 206-prec CATATGGATTACTTTGCTATGGAA TGTAAGGAAGTGTGTGGTTTT hsa-mir- TGACGGGCGAGCTTTTGGCCCGGG 232 208-prec TTATACCTGATGCTCACGTATAAG ACGAGCAAAAAGCTTGTTGGTCA hsa-mir- ACCCGGCAGTGCCTCCAGGCGCAG 233 210-prec GGCAGCCCCTGCCCACCGCACACT GCGCTGCCCCAGACCCACTGTGCG TGTGACAGCGGCTGATCTGTGCCT GGGCAGCGCGACCC hsa-mir- TCACCTGGCCATGTGACTTGTGGG 234 211-prec CTTCCCTTTGTCATCCTTCGCCTA GGGCTCTGAGCAGGGCAGGGACAG CAAAGGGGTGCTCAGTTGTCACTT CCCACAGCACGGAG hsa-mir- CGGGGCACCCCGCCCGGACAGCGC 235 212-prec GCCGGCACCTTGGCTCTAGACTGC TTACTGCCCGGGCCGCCCTCAGTA ACAGTCTCCAGTCACGGCCACCGA CGCCTGGCCCCGCC hsa-mir- CCTGTGCAGAGATTATTTTTTAAA 236 213-prec AGGTCACAATCAACATTCATTGCT GTCGGTGGGTTGAACTGTGTGGAC AAGCTCACTGAACAATGAATGCAA CTGTGGCCCCGCTT hsa-mir- GAGTTTTGAGGTTGCTTCAGTGAA 237 213-prec- CATTCAACGCTGTCGGTGAGTTTG LIM GAATTAAAATCAAAACCATCGACC GTTGATTGTACCCTATGGCTAACC ATCATCTACTCC hsa-mir- GGCCTGGCTGGACAGAGTTGTCAT 238 214-prec GTGTCTGCCTGTCTACACTTGCTG TGCAGAACATCCGCTCACCTGTAC AGCAGGCACAGACAGGCAGTCACA TGACAACCCAGCCT hsa-mir- ATCATTCAGAAATGGTATACAGGA 239 215-prec AAATGACCTATGAATTGACAGACA ATATAGCTGAGTTTGTCTGTCATT TCTTTAGGCCAATATTCTGTATGA CTGTGCTACTTCAA hsa-mir- GATGGCTGTGAGTTGGCTTAATCT 240 216-prec CAGCTGGCAACTGTGAGATGTTCA TACAATCCCTCACAGTGGTCTCTG GGATTATGCTAAACAGAGCAATTT CCTAGCCCTCACGA hsa-mir- AGTATAATTATTACATAGTTTTTG 241 217-prec ATGTCGCAGATACTGCATCAGGAA CTGATTGGATAAGAATCAGTCACC ATCAGTTCCTAATGCATTGCCTTC AGCATCTAAACAAG hsa-mir- GTGATAATGTAGCGAGATTTTCTG 242 218-1-prec TTGTGCTTGATCTAACCATGTGGT TGCGAGGTATGAGTAAAACATGGT TCCGTCAAGCACCATGGAACGTCA CGCAGCTTTCTACA hsa-mir- GACCAGTCGCTGCGGGGCTTTCCT 243 218-2-prec TTGTGCTTGATCTAACCATGTGGT GGAACGATGGAAACGGAACATGGT TCTGTCAAGCACCGCGGAAAGCAC CGTGCTCTCCTGCA hsa-mir- CCGCCCCGGGCCGCGGCTCCTGAT 244 219-prec TGTCCAAACGCAATTCTCGAGTCT ATGGCTCCGGCCGAGAGTTGAGTC TGGACGTCCCGAGCCGCCGCCCCC AAACCTCGAGCGGG hsa-mir- GACAGTGTGGCATTGTAGGGCTCC 245 220-prec ACACCGTATCTGACACTTTGGGCG AGGGCACCATGCTGAAGGTGTTCA TGATGCGGTCTGGGAACTCCTCAC GGATCTTACTGATG hsa-mir- TGAACATCCAGGTCTGGGGCATGA 246 221-prec ACCTGGCATACAATGTAGATTTCT GTGTTCGTTAGGCAACAGCTACAT TGTCTGCTGGGTTTCAGGCTACCT GGAAACATGTTCTC hsa-mir- GCTGCTGGAAGGTGTAGGTACCCT 247 222-prec CAATGGCTCAGTAGCCAGTGTAGA TCCTGTCTTTCGTAATCAGCAGCT ACATCTGGCTACTGGGTCTCTGAT GGCATCTTCTAGCT hsa-mir- CCTGGCCTCCTGCAGTGCCACGCT 248 223-prec CCGTGTATTTGACAAGCTGAGTTG GACACTCCATGTGGTAGAGTGTCA GTTTGTCAAATACCCCAAGTGCGG CACATGCTTACCAG hsa-mir- GGGCTTTCAAGTCACTAGTGGTTC 249 224-prec CGTTTAGTAGATGATTGTGCATTG TTTCAAAATGGTGCCCTAGTGACT ACAAAGCCC hsA-mir- CTTCTGGAAGCTGGTTTCACATGG 250 29b-1 = TGGCTTAGATTTTTCCATCTTTGT 102-prec1 ATCTAGCACCATTTGAAATCAGTG TTTTAGGAG hsA-mir- CTTCAGGAAGCTGGTTTCATATGG 251 29b-2 = TGGTTTAGATTTAAATAGTGATTG 102prec7.1 = TCTAGCACCATTTGAAATCAGTGT 7.2 TCTTGGGGG hsA-mir- CTTCAGGAAGCTGGTTTCATATGG 252 29b-3 = TGGTTTAGATTTAAATAGTGATTG 102prec7.1 = TCTAGCACCATTTGAAATCAGTGT 7.2 TCTTGGGGG hsa-mir- GTGAGCGACTGTAAACATCCTCGA 253 30* = mir- CTGGAAGCTGTGAAGCCACAGATG 097-prec-6 GGCTTTCAGTCGGATGTTTGCAGC TGCCTACT mir-033b ACCAAGTTTCAGTTCATGTAAACA 254 TCCTACACTCAGCTGTAATACATG GATTGGCTGGGAGGTGGATGTTTA CTTCAGCTGACTTGGA mir-101- TGCCCTGGCTCAGTTATCACAGTG 255 precursor-9 = CTGATGCTGTCTATTCTAAAGGTA mir-101-3 CAGTACTGTGATAACTGAAGGATG GCA mir-108-1- ACACTGCAAGAACAATAAGGATTT 256 small TTAGGGGCATTATGACTGAGTCAG AAAACACAGCTGCCCCTGAAAGTC CCTCATTTTTCTTGCTGT mir-108-2- ACTGCAAGAGCAATAAGGATTTTT 257 small AGGGGCATTATGATAGTGGAATGG AAACACATCTGCCCCCAAAAGTCC CTCATTTT mir-123- CGCTGGCGACGGGACATTATTACT 258 prec = mir- TTTGGTACGCGCTGTGACACTTCA 126-prec AACTCGTACCGTGAGTAATAATGC GCCGTCCACGGCA mir-123- ACATTATTACTTTTGGTACGCGCT 259 prec = mir- GTGACACTTCAAACTCGTACCGTG 126-prec AGTAATAATGCGC mir-129- TGGATCTTTTTGCGGTCTGGGCTT 260 1-prec GCTGTTCCTCTCAACAGTAGTCAG GAAGCCCTTACCCCAAAAAGTATC TA mir-129- TGCCCTTCGCGAATCTTTTTGCGG 261 small-2-129b? TCTGGGCTTGCTGTACATAACTCA ATAGCCGGAAGCCCTTACCCCAAA AAGCATTTGCGGAGGGCG mir-133b- GCCCCCTGCTCTGGCTGGTCAAAC 262 small GGAACCAAGTCCGTCTTCCTGAGA GGTTTGGTCCCCTTCAACCAGCTA CAGCAGGG mir-135- AGATAAATTCACTCTAGTGCTTTA 263 small-2 TGGCTTTTTATTCCTATGTGATAG TAATAAAGTCTCATGTAGGGATGG AAGCCATGAAATACATTGTGAAAA ATCA mir-148b- AAGCACGATTAGCATTTGAGGTGA 264 small AGTTCTGTTATACACTCAGGCTGT GGCTCTCTGAAAGTCAGTGCAT mir-151- CCTGTCCTCAAGGAGCTTCAGTCT 265 prec AGTAGGGGATGAGACATACTAGAC TGTGAGCTCCTCGAGGGCAGG mir-155- CTGTTAATGCTAATCGTGATAGGG 266 prec(BIC) GTTTTTGCCTCCAACTGACTCCTA CATATTAGCATTAACAG mir-156 = CCTAACACTGTCTGGTAAAGATGG 267 mir-157 = CTCCCGGGTGGGTTCTCTCGGCAG overlap TAACCTTCAGGGAGCCCTGAAGAC mir-141 CATGGAGGAC mir-158- GCCGAGACCGAGTGCACAGGGCTC 268 small = TGACCTATGAATTGACAGCCAGTG mir-192 CTCTCGTCTCCCCTCTGGCTGCCA ATTCCATAGGTCACAGGTATGTTC GCCTCAATGCCAGC mir-159- TCCCGCCCCCTGTAACAGCAACTC 269 1-small CATGTGGAAGTGCCCACTGGTTCC AGTGGGGCTGCTGTTATCTGGGGC GAGGGCCA mir-161- AAAGCTGGGTTGAGAGGGCGAAAA 270 small AGGATGAGGTGACTGGTCTGGGCT ACGCTATGCTGCGGCGCTCGGG mir-163- CATTGGCCTCCTAAGCCAGGGATT 271 1b-small GTGGGTTCGAGTCCCACCCGGGGT AAAGAAAGGCCGAATT mir-163- CCTAAGCCAGGGATTGTGGGTTCG 272 3-small AGTCCCACCTGGGGTAGAGGTGAA AGTTCCTTTTACGGAATTTTTT mir-175- GGGCTTTCAAGTCACTAGTGGTTC 273 small = CGTTTAGTAGATGATTGTGCATTG mir-224 TTTCAAAATGGTGCCCTAGTGACT ACAAAGCCC mir-177- ACGCAAGTGTCCTAAGGTGAGCTC 274 small AGGGAGCACAGAAACCTCCAGTGG AACAGAAGGGCAAAAGCTCATT mir-180- CATGTGTCACTTTCAGGTGGAGTT 275 small TCAAGAGTCCCTTCCTGGTTCACC GTCTCCTTTGCTCTTCCACAAC mir-187- GGTCGGGCTCACCATGACACAGTG 276 prec TGAGACTCGGGCTACAACACAGGA CCCGGGGCGCTGCTCTGACCCCTC GTGTCTTGTGTTGCAGCCGGAGGG ACGCAGGTCCGCA mir-188- TGCTCCCTCTCTCACATCCCTTGC 277 prec ATGGTGGAGGGTGAGCTTTCTGAA AACCCCTCCCACATGCAGGGTTTG CAGGATGGCGAGCC mir-190- TGCAGGCCTCTGTGTGATATGTTT 278 prec GATATATTAGGTTGTTATTTAATC CAACTATATATCAAACATATTCCT ACAGTGTCTTGCC mir-197-2 GTGCATGTGTATGTATGTGTGCAT 279 GTGCATGTGTATGTGTATGAGTGC ATGCGTGTGTGC mir-197- GGCTGTGCCGGGTAGAGAGGGCAG 280 prec TGGGAGGTAAGAGCTCTTCACCCT TCACCACCTTCTCCACCCAGCATG GCC mir-202- GTTCCTTTTTCCTATGCATATACT 281 prec TCTTTGAGGATCTGGCCTAAAGAG GTATAGGGCATGGGAAGATGGAGC mir-294-1 CAATCTTCCTTTATCATGGTATTG 282 (chr16) ATTTTTCAGTGCTTCCCTTTTGTG TGAGAGAAGATA mir-hesl ATGGAGCTGCTCACCCTGTGGGCC 283 TCAAATGTGGAGGAACTATTCTGA TGTCCAAGTGGAAAGTGCTGCGAC ATTTGAGCGTCACCGGTGACGCCC ATATCA mir-hes2 GCATCCCCTCAGCCTGTGGCACTC 284 AAACTGTGGGGGCACTTTCTGCTC TCTGGTGAAAGTGCCGCCATCTTT TGAGTGTTACCGCTTGAGAAGACT CAACC mir-hes3 CGAGGAGCTCATACTGGGATACTC 285 AAAATGGGGGCGCTTTCCTTTTTG TCTGTTACTGGGAAGTGCTTCGAT TTTGGGGTGTCCCTGTTTGAGTAG GGCATC hsa-mir- CTTCAGGAAGCTGGTTTCATATGG 286 29b-1 TGGTTTAGATTTAAATAGTGATTG TCTAGCACCATTTGAAATCAGTGT TCTTGGGGG *An underlined sequence within a precursor sequence represents a processed miR transcript. All sequences are human.

The level of at least one miR gene product can be measured in cells of a biological sample obtained from the subject. For example, a tissue sample can be removed from a subject suspected of having breast cancer associated with by conventional biopsy techniques. In another example, a blood sample can be removed from the subject, and white blood cells can be isolated for DNA extraction by standard techniques. The blood or tissue sample is preferably obtained from the subject prior to initiation of radiotherapy, chemotherapy or other therapeutic treatment. A corresponding control tissue or blood sample can be obtained from unaffected tissues of the subject, from a normal human individual or population of normal individuals, or from cultured cells corresponding to the majority of cells in the subject's sample. The control tissue or blood sample is then processed along with the sample from the subject, so that the levels of miR gene product produced from a given miR gene in cells from the subject's sample can be compared to the corresponding miR gene product levels from cells of the control sample.

An alteration (i.e., an increase or decrease) in the level of a miR gene product in the sample obtained from the subject, relative to the level of a corresponding miR gene product in a control sample, is indicative of the presence of breast cancer in the subject. In one embodiment, the level of the at least one miR gene product in the test sample is greater than the level of the corresponding miR gene product in the control sample (i.e., expression of the miR gene product is “up-regulated”). As used herein, expression of a miR gene product is “up-regulated” when the amount of miR gene product in a cell or tissue sample from a subject is greater than the amount the same gene product in a control cell or tissue sample. In another embodiment, the level of the at least one miR gene product in the test sample is less than the level of the corresponding miR gene product in the control sample (i.e., expression of the miR gene product is “down-regulated”). As used herein, expression of a miR gene is “down-regulated” when the amount of miR gene product produced from that gene in a cell or tissue sample from a subject is less than the amount produced from the same gene in a control cell or tissue sample. The relative miR gene expression in the control and normal samples can be determined with respect to one or more RNA expression standards. The standards can comprise, for example, a zero miR gene expression level, the miR gene expression level in a standard cell line, or the average level of miR gene expression previously obtained for a population of normal human controls.

The level of a miR gene product in a sample can be measured using any technique that is suitable for detecting RNA expression levels in a biological sample. Suitable techniques for determining RNA expression levels in cells from a biological sample (for example, Northern blot analysis, RT-PCR, in situ hybridization) are well known to those of skill in the art. In a particular embodiment, the level of at least one miR gene product is detected using Northern blot analysis. For example, total cellular RNA can be purified from cells by homogenization in the presence of nucleic acid extraction buffer, followed by centrifugation. Nucleic acids are precipitated, and DNA is removed by treatment with DNase and precipitation. The RNA molecules are then separated by gel electrophoresis on agarose gels according to standard techniques, and transferred to nitrocellulose filters. The RNA is then immobilized on the filters by heating. Detection and quantification of specific RNA is accomplished using appropriately labeled DNA or RNA probes complementary to the RNA in question. See, for example, Molecular Cloning: A Laboratory Manual, J. Sambrook et al., eds., 2nd edition, Cold Spring Harbor Laboratory Press, 1989, Chapter 7, the entire disclosure of which is incorporated by reference.

Suitable probes for Northern blot hybridization of a given miR gene product can be produced from the nucleic acid sequences provided in Table 1. Methods for preparation of labeled DNA and RNA probes, and the conditions for hybridization thereof to target nucleotide sequences, are described in Molecular Cloning: A Laboratory Manual, J. Sambrook et al., eds., 2nd edition, Cold Spring Harbor Laboratory Press, 1989, Chapters 10 and 11, the disclosures of which are incorporated herein by reference.

For example, the nucleic acid probe can be labeled with, for example, a radionuclide, such as 3H, 32P, 33P, 14C, or 35S; a heavy metal; or a ligand capable of functioning as a specific binding pair member for a labeled ligand (for example, biotin, avidin or an antibody), a fluorescent molecule, a chemiluminescent molecule, an enzyme or the like.

Probes can be labeled to high specific activity by either the nick translation method of Rigby et al. (1977), J. Mol. Biol. 113:237-251 or by the random priming method of Fienberg et al. (1983), Anal. Biochem. 132:6-13, the entire disclosures of which are incorporated herein by reference. The latter is the method of choice for synthesizing 32P-labeled probes of high specific activity from single-stranded DNA or from RNA templates. For example, by replacing preexisting nucleotides with highly radioactive nucleotides according to the nick translation method, it is possible to prepare 32P-labeled nucleic acid probes with a specific activity well in excess of 108 cpm/microgram. Autoradiographic detection of hybridization can then be performed by exposing hybridized filters to photographic film. Densitometric scanning of the photographic films exposed by the hybridized filters provides an accurate measurement of miR gene transcript levels. Using another approach, miR gene transcript levels can be quantified by computerized imaging systems, such the Molecular Dynamics 400-B 2D Phosphorimager available from Amersham Biosciences, Piscataway, N.J.

Where radionuclide labeling of DNA or RNA probes is not practical, the random-primer method can be used to incorporate an analogue, for example, the dTTP analogue 5-(N—(N-biotinyl-epsilon-aminocaproyl)-3-aminoallyl)deoxyuridine triphosphate, into the probe molecule. The biotinylated probe oligonucleotide can be detected by reaction with biotin-binding proteins, such as avidin, streptavidin, and antibodies (for example, anti-biotin antibodies) coupled to fluorescent dyes or enzymes that produce color reactions.

In addition to Northern and other RNA hybridization techniques, determining the levels of RNA transcripts can be accomplished using the technique of in situ hybridization. This technique requires fewer cells than the Northern blotting technique, and involves depositing whole cells onto a microscope cover slip and probing the nucleic acid content of the cell with a solution containing radioactive or otherwise labeled nucleic acid (for example, cDNA or RNA) probes. This technique is particularly well-suited for analyzing tissue biopsy samples from subjects. The practice of the in situ hybridization technique is described in more detail in U.S. Pat. No. 5,427,916, the entire disclosure of which is incorporated herein by reference. Suitable probes for in situ hybridization of a given miR gene product can be produced from the nucleic acid sequences provided in Table 1, as described above.

The relative number of miR gene transcripts in cells can also be determined by reverse transcription of miR gene transcripts, followed by amplification of the reverse-transcribed transcripts by polymerase chain reaction (RT-PCR). The levels of miR gene transcripts can be quantified in comparison with an internal standard, for example, the level of mRNA from a “housekeeping” gene present in the same sample. A suitable “housekeeping” gene for use as an internal standard includes, for example, myosin or glyceraldehyde-3-phosphate dehydrogenase (G3PDH). The methods for quantitative RT-PCR and variations thereof are within the skill in the art.

In some instances, it may be desirable to simultaneously determine the expression level of a plurality of different miR gene products in a sample. In other instances, it may be desirable to determine the expression level of the transcripts of all known miR genes correlated with a cancer. Assessing cancer-specific expression levels for hundreds of miR genes is time consuming and requires a large amount of total RNA (at least 20 μg for each Northern blot) and autoradiographic techniques that require radioactive isotopes.

To overcome these limitations, an oligolibrary, in microchip format (i.e., a microarray), may be constructed containing a set of probe oligodeoxynucleotides that are specific for a set of miR genes. Using such a microarray, the expression level of multiple microRNAs in a biological sample can be determined by reverse transcribing the RNAs to generate a set of target oligodeoxynucleotides, and hybridizing them to probe oligodeoxynucleotides on the microarray to generate a hybridization, or expression, profile. The hybridization profile of the test sample can then be compared to that of a control sample to determine which microRNAs have an altered expression level in breast cancer cells. As used herein, “probe oligonucleotide” or “probe oligodeoxynucleotide” refers to an oligonucleotide that is capable of hybridizing to a target oligonucleotide. “Target oligonucleotide” or “target oligodeoxynucleotide” refers to a molecule to be detected (for example, via hybridization). By “miR-specific probe oligonucleotide” or “probe oligonucleotide specific for a miR” is meant a probe oligonucleotide that has a sequence selected to hybridize to a specific miR gene product, or to a reverse transcript of the specific miR gene product.

An “expression profile” or “hybridization profile” of a particular sample is essentially a fingerprint of the state of the sample; while two states may have any particular gene similarly expressed, the evaluation of a number of genes simultaneously allows the generation of a gene expression profile that is unique to the state of the cell. That is, normal tissue may be distinguished from breast cancer tissue, and within breast cancer tissue, different prognosis states (good or poor long term survival prospects, for example) may be determined. By comparing expression profiles of breast cancer tissue in different states, information regarding which genes are important (including both up- and down-regulation of genes) in each of these states is obtained. The identification of sequences that are differentially expressed in breast cancer tissue or normal breast tissue, as well as differential expression resulting in different prognostic outcomes, allows the use of this information in a number of ways. For example, a particular treatment regime may be evaluated (for example, to determine whether a chemotherapeutic drug act to improve the long-term prognosis in a particular patient). Similarly, diagnosis may be done or confirmed by comparing patient samples with the known expression profiles. Furthermore, these gene expression profiles (or individual genes) allow screening of drug candidates that suppress the breast cancer expression profile or convert a poor prognosis profile to a better prognosis profile.

Accordingly, the invention provides methods of diagnosing whether a subject has, or is at risk for developing, breast cancer, comprising reverse transcribing RNA from a test sample obtained from the subject to provide a set of target oligo-deoxynucleotides, hybridizing the target oligo-deoxynucleotides to a microarray comprising miRNA-specific probe oligonucleotides to provide a hybridization profile for the test sample, and comparing the test sample hybridization profile to a hybridization profile generated from a control sample, wherein an alteration in the signal of at least one miRNA is indicative of the subject either having, or being at risk for developing, breast cancer. In one embodiment, the microarray comprises miRNA-specific probe oligonucleotides for a substantial portion of the human miRNome. In a particular embodiment, the microarray comprises miRNA-specific probe oligo-nucleotides for one or more miRNAs selected from the group consisting of miR-125b, miR-145, miR-21, miR-155, miR-10b, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, miR-213, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, let-7i (let-7d-v2), miR-101-1, miR-122a, miR-128b, miR-136, miR-143, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210 and combinations thereof. In a further embodiment, the at least one miR gene product is selected from the group consisting of miR-125b, miR-145, miR-21, miR-155, miR-10b and combinations thereof.

The microarray can be prepared from gene-specific oligonucleotide probes generated from known miRNA sequences. The array may contain two different oligonucleotide probes for each miRNA, one containing the active, mature sequence and the other being specific for the precursor of the miRNA. The array may also contain controls, such as one or more mouse sequences differing from human orthologs by only a few bases, which can serve as controls for hybridization stringency conditions. tRNAs from both species may also be printed on the microchip, providing an internal, relatively stable, positive control for specific hybridization. One or more appropriate controls for non-specific hybridization may also be included on the microchip. For this purpose, sequences are selected based upon the absence of any homology with any known miRNAs.

The microarray may be fabricated using techniques known in the art. For example, probe oligonucleotides of an appropriate length, for example, 40 nucleotides, are 5′-amine modified at position C6 and printed using commercially available microarray systems, for example, the GeneMachine OmniGrid™ 100 Microarrayer and Amersham CodeLink™ activated slides. Labeled cDNA oligomer corresponding to the target RNAs is prepared by reverse transcribing the target RNA with labeled primer. Following first strand synthesis, the RNA/DNA hybrids are denatured to degrade the RNA templates. The labeled target cDNAs thus prepared are then hybridized to the microarray chip under hybridizing conditions, for example, 6×SSPE/30% formamide at 25° C. for 18 hours, followed by washing in 0.75×TNT at 37° C. for 40 minutes. At positions on the array where the immobilized probe DNA recognizes a complementary target cDNA in the sample, hybridization occurs. The labeled target cDNA marks the exact position on the array where binding occurs, allowing automatic detection and quantification. The output consists of a list of hybridization events, indicating the relative abundance of specific cDNA sequences, and therefore the relative abundance of the corresponding complementary miRs, in the patient sample. According to one embodiment, the labeled cDNA oligomer is a biotin-labeled cDNA, prepared from a biotin-labeled primer. The microarray is then processed by direct detection of the biotin-containing transcripts using, for example, Streptavidin-Alexa647 conjugate, and scanned utilizing conventional scanning methods. Image intensities of each spot on the array are proportional to the abundance of the corresponding miR in the patient sample.

The use of the array has several advantages for miRNA expression detection. First, the global expression of several hundred genes can be identified in the same sample at one time point. Second, through careful design of the oligonucleotide probes, expression of both mature and precursor molecules can be identified. Third, in comparison with Northern blot analysis, the chip requires a small amount of RNA, and provides reproducible results using 2.5 μg of total RNA. The relatively limited number of miRNAs (a few hundred per species) allows the construction of a common microarray for several species, with distinct oligonucleotide probes for each. Such a tool would allow for analysis of trans-species expression for each known miR under various conditions.

In addition to use for quantitative expression level assays of specific miRs, a microchip containing miRNA-specific probe oligonucleotides corresponding to a substantial portion of the miRNome, preferably the entire miRNome, may be employed to carry out miR gene expression profiling, for analysis of miR expression patterns. Distinct miR signatures can be associated with established disease markers, or directly with a disease state.

According to the expression profiling methods described herein, total RNA from a sample from a subject suspected of having a cancer (such as breast cancer) is quantitatively reverse transcribed to provide a set of labeled target oligodeoxynucleotides complementary to the RNA in the sample. The target oligodeoxynucleotides are then hybridized to a microarray comprising miRNA-specific probe oligonucleotides to provide a hybridization profile for the sample. The result is a hybridization profile for the sample representing the expression pattern of miRNA in the sample. The hybridization profile comprises the signal from the binding of the target oligodeoxynucleotides from the sample to the miRNA-specific probe oligonucleotides in the microarray. The profile may be recorded as the presence or absence of binding (signal vs. zero signal). More preferably, the profile recorded includes the intensity of the signal from each hybridization. The profile is compared to the hybridization profile generated from a normal, noncancerous, control sample. An alteration in the signal is indicative of the presence of the cancer in the subject.

Other techniques for measuring miR gene expression are also within the skill in the art, and include various techniques for measuring rates of RNA transcription and degradation.

The invention also provides methods of diagnosing a breast cancer associated with one or more prognostic markers, comprising measuring the level of at least one miR gene product in a breast cancer test sample from a subject and comparing the level of the at least one miR gene product in the breast cancer test sample to the level of a corresponding miR gene product in a control sample. An alteration (for example, an increase, a decrease) in the signal of at least one miRNA in the test sample relative to the control sample is indicative of the subject either having, or being at risk for developing, breast cancer associated with the one or more prognostic markers.

The breast cancer can be associated with one or more prognostic markers or features, including, a marker associated with an adverse (negative) prognosis, or a marker associated with a good (positive) prognosis. In certain embodiments, the breast cancer that is diagnosed using the methods described herein is associated with one or more adverse prognostic features selected from the group consisting of estrogen receptor expression, progesterone receptor expression, positive lymph node metastasis, high proliferative index, detectable p53 expression, advanced tumor stage, and high vascular invasion. Particular microRNAs whose expression is altered in breast cancer cells associated with each of these prognostic markers are described herein (see, for example, Example 3 and FIG. 4). In one embodiment, the level of the at least one miR gene product is measured by reverse transcribing RNA from a test sample obtained from the subject to provide a set of target oligodeoxynucleotides, hybridizing the target oligodeoxynucleotides to a microarray that comprises miRNA-specific probe oligonucleotides to provide a hybridization profile for the test sample, and comparing the test sample hybridization profile to a hybridization profile generated from a control sample.

Without wishing to be bound by any one theory, it is believed that alterations in the level of one or more miR gene products in cells can result in the deregulation of one or more intended targets for these miRs, which can lead to the formation of breast cancer. Therefore, altering the level of the miR gene product (for example, by decreasing the level of a miR that is up-regulated in breast cancer cells and/or by increasing the level of a miR that is down-regulated in cancer cells) may successfully treat the breast cancer. Examples of putative gene targets for miRNAs that are deregulated in breast cancer tissues are described herein (see, for example, Example 2 and Table 4).

Accordingly, the present invention encompasses methods of treating breast cancer in a subject, wherein at least one miR gene product is de-regulated (for example, down-regulated or up-regulated) in the cancer cells of the subject. When the at least one isolated miR gene product is down-regulated in the breast cancer cells, the method comprises administering an effective amount of the at least one isolated miR gene product, provided that the miR gene is not miR15 or miR16, such that proliferation of cancer cells in the subject is inhibited. When the at least one isolated miR gene product is up-regulated in the cancer cells, the method comprises administering to the subject an effective amount of at least one compound for inhibiting expression of the at least one miR gene, referred to herein as miR gene expression inhibition compounds, such that proliferation of breast cancer cells is inhibited.

The terms “treat”, “treating” and “treatment”, as used herein, refer to ameliorating symptoms associated with a disease or condition, for example, breast cancer, including preventing or delaying the onset of the disease symptoms, and/or lessening the severity or frequency of symptoms of the disease or condition. The terms “subject” and “individual” are defined herein to include animals, such as mammals, including but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent, or murine species. In a preferred embodiment, the animal is a human.

As used herein, an “effective amount” of an isolated miR gene product is an amount sufficient to inhibit proliferation of a cancer cell in a subject suffering from breast cancer. One skilled in the art can readily determine an effective amount of an miR gene product to be administered to a given subject, by taking into account factors, such as the size and weight of the subject; the extent of disease penetration; the age, health and sex of the subject; the route of administration; and whether the administration is regional or systemic.

For example, an effective amount of an isolated miR gene product can be based on the approximate weight of a tumor mass to be treated. The approximate weight of a tumor mass can be determined by calculating the approximate volume of the mass, wherein one cubic centimeter of volume is roughly equivalent to one gram. An effective amount of the isolated miR gene product based on the weight of a tumor mass can be in the range of about 10-500 micrograms/gram of tumor mass. In certain embodiments, the tumor mass can be at least about 10 micrograms/gram of tumor mass, at least about 60 micrograms/gram of tumor mass or at least about 100 micrograms/gram of tumor mass.

An effective amount of an isolated miR gene product can also be based on the approximate or estimated body weight of a subject to be treated. Preferably, such effective amounts are administered parenterally or enterally, as described herein. For example, an effective amount of the isolated miR gene product is administered to a subject can range from about 5-3000 micrograms/kg of body weight, from about 700-1000 micrograms/kg of body weight, or greater than about 1000 micrograms/kg of body weight.

One skilled in the art can also readily determine an appropriate dosage regimen for the administration of an isolated miR gene product to a given subject. For example, a miR gene product can be administered to the subject once (for example, as a single injection or deposition). Alternatively, a miR gene product can be administered once or twice daily to a subject for a period of from about three to about twenty-eight days, more particularly from about seven to about ten days. In a particular dosage regimen, a miR gene product is administered once a day for seven days. Where a dosage regimen comprises multiple administrations, it is understood that the effective amount of the miR gene product administered to the subject can comprise the total amount of gene product administered over the entire dosage regimen.

As used herein, an “isolated” miR gene product is one which is synthesized, or altered or removed from the natural state through human intervention. For example, a synthetic miR gene product, or a miR gene product partially or completely separated from the coexisting materials of its natural state, is considered to be “isolated.” An isolated miR gene product can exist in substantially-purified form, or can exist in a cell into which the miR gene product has been delivered. Thus, a miR gene product which is deliberately delivered to, or expressed in, a cell is considered an “isolated” miR gene product. A miR gene product produced inside a cell from a miR precursor molecule is also considered to be “isolated” molecule.

Isolated miR gene products can be obtained using a number of standard techniques. For example, the miR gene products can be chemically synthesized or recombinantly produced using methods known in the art. In one embodiment, miR gene products are chemically synthesized using appropriately protected ribonucleoside phosphoramidites and a conventional DNA/RNA synthesizer. Commercial suppliers of synthetic RNA molecules or synthesis reagents include, for example, Proligo (Hamburg, Germany), Dharmacon Research (Lafayette, Colo., U.S.A.), Pierce Chemical (part of Perbio Science, Rockford, Ill., U.S.A.), Glen Research (Sterling, Va., U.S.A.), ChemGenes (Ashland, Mass., U.S.A.) and Cruachem (Glasgow, UK).

Alternatively, the miR gene products can be expressed from recombinant circular or linear DNA plasmids using any suitable promoter. Suitable promoters for expressing RNA from a plasmid include, for example, the U6 or H1 RNA pol III promoter sequences, or the cytomegalovirus promoters. Selection of other suitable promoters is within the skill in the art. The recombinant plasmids of the invention can also comprise inducible or regulatable promoters for expression of the miR gene products in cancer cells.

The miR gene products that are expressed from recombinant plasmids can be isolated from cultured cell expression systems by standard techniques. The miR gene products which are expressed from recombinant plasmids can also be delivered to, and expressed directly in, the cancer cells. The use of recombinant plasmids to deliver the miR gene products to cancer cells is discussed in more detail below.

The miR gene products can be expressed from a separate recombinant plasmid, or they can be expressed from the same recombinant plasmid. In one embodiment, the miR gene products are expressed as RNA precursor molecules from a single plasmid, and the precursor molecules are processed into the functional miR gene product by a suitable processing system, including, but not limited to, processing systems extant within a cancer cell. Other suitable processing systems include, for example, the in vitro Drosophila cell lysate system (for example, as described in U.S. Published Patent Application No. 2002/0086356 to Tuschl et al., the entire disclosure of which are incorporated herein by reference) and the E. coli RNAse III system (for example, as described in U.S. Published Patent Application No. 2004/0014113 to Yang et al., the entire disclosure of which are incorporated herein by reference).

Selection of plasmids suitable for expressing the miR gene products, methods for inserting nucleic acid sequences into the plasmid to express the gene products, and methods of delivering the recombinant plasmid to the cells of interest are within the skill in the art. See, for example, Zeng et al. (2002), Molecular Cell 9:1327-1333; Tuschl (2002), Nat. Biotechnol, 20:446-448; Brummelkamp et al. (2002), Science 296:550-553; Miyagishi et al. (2002), Nat. Biotechnol. 20:497-500; Paddison et al. (2002), Genes Dev. 16:948-958; Lee et al. (2002), Nat. Biotechnol. 20:500-505; and Paul et al. (2002), Nat. Biotechnol. 20:505-508, the entire disclosures of which are incorporated herein by reference.

In one embodiment, a plasmid expressing the miR gene products comprises a sequence encoding a miR precursor RNA under the control of the CMV intermediate-early promoter. As used herein, “under the control” of a promoter means that the nucleic acid sequences encoding the miR gene product are located 3′ of the promoter, so that the promoter can initiate transcription of the miR gene product coding sequences.

The miR gene products can also be expressed from recombinant viral vectors. It is contemplated that the miR gene products can be expressed from two separate recombinant viral vectors, or from the same viral vector. The RNA expressed from the recombinant viral vectors can either be isolated from cultured cell expression systems by standard techniques, or can be expressed directly in cancer cells. The use of recombinant viral vectors to deliver the miR gene products to cancer cells is discussed in more detail below.

The recombinant viral vectors of the invention comprise sequences encoding the miR gene products and any suitable promoter for expressing the RNA sequences. Suitable promoters include, for example, the U6 or H1 RNA pol III promoter sequences, or the cytomegalovirus promoters. Selection of other suitable promoters is within the skill in the art. The recombinant viral vectors of the invention can also comprise inducible or regulatable promoters for expression of the miR gene products in a cancer cell.

Any viral vector capable of accepting the coding sequences for the miR gene products can be used; for example, vectors derived from adenovirus (AV); adeno-associated virus (AAV); retroviruses (for example, lentiviruses (LV), Rhabdoviruses, murine leukemia virus); herpes virus, and the like. The tropism of the viral vectors can be modified by pseudotyping the vectors with envelope proteins or other surface antigens from other viruses, or by substituting different viral capsid proteins, as appropriate.

For example, lentiviral vectors of the invention can be pseudotyped with surface proteins from vesicular stomatitis virus (VSV), rabies, Ebola, Mokola, and the like. AAV vectors of the invention can be made to target different cells by engineering the vectors to express different capsid protein serotypes. For example, an AAV vector expressing a serotype 2 capsid on a serotype 2 genome is called AAV 2/2. This serotype 2 capsid gene in the AAV 2/2 vector can be replaced by a serotype 5 capsid gene to produce an AAV 2/5 vector. Techniques for constructing AAV vectors that express different capsid protein serotypes are within the skill in the art; see, for example, Rabinowitz, J. E., et al. (2002), J. Virol. 76:791-801, the entire disclosure of which is incorporated herein by reference.

Selection of recombinant viral vectors suitable for use in the invention, methods for inserting nucleic acid sequences for expressing RNA into the vector, methods of delivering the viral vector to the cells of interest, and recovery of the expressed RNA products are within the skill in the art. See, for example, Dornburg (1995), Gene Therap. 2:301-310; Eglitis (1988), Biotechniques 6:608-614; Miller (1990), Hum. Gene Therap. 1:5-14; and Anderson (1998), Nature 392:25-30, the entire disclosures of which are incorporated herein by reference.

Particularly suitable viral vectors are those derived from AV and AAV. A suitable AV vector for expressing the miR gene products, a method for constructing the recombinant AV vector, and a method for delivering the vector into target cells, are described in Xia et al. (2002), Nat. Biotech. 20:1006-1010, the entire disclosure of which is incorporated herein by reference. Suitable AAV vectors for expressing the miR gene products, methods for constructing the recombinant AAV vector, and methods for delivering the vectors into target cells are described in Samulski et al. (1987), J. Virol. 61:3096-3101; Fisher et al. (1996), J. Virol., 70:520-532; Samulski et al. (1989), J. Virol. 63:3822-3826; U.S. Pat. No. 5,252,479; U.S. Pat. No. 5,139,941; International Patent Application No. WO 94/13788; and International Patent Application No. WO 93/24641, the entire disclosures of which are incorporated herein by reference. In one embodiment, the miR gene products are expressed from a single recombinant AAV vector comprising the CMV intermediate early promoter.

In a certain embodiment, a recombinant AAV viral vector of the invention comprises a nucleic acid sequence encoding a miR precursor RNA in operable connection with a polyT termination sequence under the control of a human U6 RNA promoter. As used herein, “in operable connection with a polyT termination sequence” means that the nucleic acid sequences encoding the sense or antisense strands are immediately adjacent to the polyT termination signal in the 5′ direction. During transcription of the miR sequences from the vector, the polyT termination signals act to terminate transcription.

In other embodiments of the treatment methods of the invention, an effective amount of at least one compound which inhibits miR expression can also be administered to the subject. As used herein, “inhibiting miR expression” means that the production of the active, mature form of miR gene product after treatment is less than the amount produced prior to treatment. One skilled in the art can readily determine whether miR expression has been inhibited in a cancer cell, using for example the techniques for determining miR transcript level discussed above for the diagnostic method Inhibition can occur at the level of gene expression (such as, by inhibiting transcription of a miR gene encoding the miR gene product) or at the level of processing (such as, by inhibiting processing of a miR precursor into a mature, active miR).

As used herein, an “effective amount” of a compound that inhibits miR expression is an amount sufficient to inhibit proliferation of a cancer cell in a subject suffering from a cancer associated with a cancer-associated chromosomal feature. One skilled in the art can readily determine an effective amount of an miR expression-inhibiting compound to be administered to a given subject, by taking into account factors, such as the size and weight of the subject; the extent of disease penetration; the age, health and sex of the subject; the route of administration; and whether the administration is regional or systemic.

For example, an effective amount of the expression-inhibiting compound can be based on the approximate weight of a tumor mass to be treated. The approximate weight of a tumor mass can be determined by calculating the approximate volume of the mass, wherein one cubic centimeter of volume is roughly equivalent to one gram. An effective amount based on the weight of a tumor mass can be between about 10-500 micrograms/gram of tumor mass, at least about 10 micrograms/gram of tumor mass, at least about 60 micrograms/gram of tumor mass, and at least about 100 micrograms/gram of tumor mass.

An effective amount of a compound that inhibits miR expression can also be based on the approximate or estimated body weight of a subject to be treated. Such effective amounts are administered parenterally or enterally, among others, as described herein. For example, an effective amount of the expression-inhibiting compound administered to a subject can range from about 5-3000 micrograms/kg of body weight, from about 700-1000 micrograms/kg of body weight, or it can be greater than about 1000 micrograms/kg of body weight.

One skilled in the art can also readily determine an appropriate dosage regimen for administering a compound that inhibits miR expression to a given subject. For example, an expression-inhibiting compound can be administered to the subject once (for example, as a single injection or deposition). Alternatively, an expression-inhibiting compound can be administered once or twice daily to a subject for a period of from about three to about twenty-eight days, more preferably from about seven to about ten days. In a particular dosage regimen, an expression-inhibiting compound is administered once a day for seven days. Where a dosage regimen comprises multiple administrations, it is understood that the effective amount of the expression-inhibiting compound administered to the subject can comprise the total amount of compound administered over the entire dosage regimen.

Suitable compounds for inhibiting miR gene expression include double-stranded RNA (such as short- or small-interfering RNA or “siRNA”), antisense nucleic acids, and enzymatic RNA molecules, such as ribozymes. Each of these compounds can be targeted to a given miR gene product and destroy or induce the destruction of the target miR gene product.

For example, expression of a given miR gene can be inhibited by inducing RNA interference of the miR gene with an isolated double-stranded RNA (“dsRNA”) molecule which has at least 90%, for example at least 95%, at least 98%, at least 99% or 100%, sequence homology with at least a portion of the miR gene product. In a particular embodiment, the dsRNA molecule is a “short or small interfering RNA” or “siRNA.”

siRNA useful in the present methods comprise short double-stranded RNA from about 17 nucleotides to about 29 nucleotides in length, preferably from about 19 to about 25 nucleotides in length. The siRNA comprise a sense RNA strand and a complementary antisense RNA strand annealed together by standard Watson-Crick base-pairing interactions (hereinafter “base-paired”). The sense strand comprises a nucleic acid sequence which is substantially identical to a nucleic acid sequence contained within the target miR gene product.

As used herein, a nucleic acid sequence in a siRNA which is “substantially identical” to a target sequence contained within the target mRNA is a nucleic acid sequence that is identical to the target sequence, or that differs from the target sequence by one or two nucleotides. The sense and antisense strands of the siRNA can comprise two complementary, single-stranded RNA molecules, or can comprise a single molecule in which two complementary portions are base-paired and are covalently linked by a single-stranded “hairpin” area.

The siRNA can also be altered RNA that differs from naturally-occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations can include addition of non-nucleotide material, such as to the end(s) of the siRNA or to one or more internal nucleotides of the siRNA, or modifications that make the siRNA resistant to nuclease digestion, or the substitution of one or more nucleotides in the siRNA with deoxyribonucleotides.

One or both strands of the siRNA can also comprise a 3′ overhang. As used herein, a “3′ overhang” refers to at least one unpaired nucleotide extending from the 3′-end of a duplexed RNA strand. Thus, in certain embodiments, the siRNA comprises at least one 3′ overhang of from 1 to about 6 nucleotides (which includes ribonucleotides or deoxyribonucleotides) in length, from 1 to about 5 nucleotides in length, from 1 to about 4 nucleotides in length, or from about 2 to about 4 nucleotides in length. In a particular embodiment, the 3′ overhang is present on both strands of the siRNA, and is 2 nucleotides in length. For example, each strand of the siRNA can comprise 3′ overhangs of dithymidylic acid (“TT”) or diuridylic acid (“uu”).

The siRNA can be produced chemically or biologically, or can be expressed from a recombinant plasmid or viral vector, as described above for the isolated miR gene products. Exemplary methods for producing and testing dsRNA or siRNA molecules are described in U.S. Published Patent Application No. 2002/0173478 to Gewirtz and in U.S. Pat. No. 7,148,342 to Reich et al., the entire disclosures of which are incorporated herein by reference.

Expression of a given miR gene can also be inhibited by an antisense nucleic acid. As used herein, an “antisense nucleic acid” refers to a nucleic acid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-peptide nucleic acid interactions, which alters the activity of the target RNA. Antisense nucleic acids suitable for use in the present methods are single-stranded nucleic acids (for example, RNA, DNA, RNA-DNA chimeras, PNA) that generally comprise a nucleic acid sequence complementary to a contiguous nucleic acid sequence in an miR gene product. The antisense nucleic acid can comprise a nucleic acid sequence that is 50-100% complementary, 75-100% complementary, or 95-100% complementary to a contiguous nucleic acid sequence in an miR gene product. Nucleic acid sequences for the miR gene products are provided in Table 1. Without wishing to be bound by any theory, it is believed that the antisense nucleic acids activate RNase H or another cellular nuclease that digests the miR gene product/antisense nucleic acid duplex.

Antisense nucleic acids can also contain modifications to the nucleic acid backbone or to the sugar and base moieties (or their equivalent) to enhance target specificity, nuclease resistance, delivery or other properties related to efficacy of the molecule. Such modifications include cholesterol moieties, duplex intercalators, such as acridine, or one or more nuclease-resistant groups.

Antisense nucleic acids can be produced chemically or biologically, or can be expressed from a recombinant plasmid or viral vector, as described above for the isolated miR gene products. Exemplary methods for producing and testing are within the skill in the art; see, for example, Stein and Cheng (1993), Science 261:1004 and U.S. Pat. No. 5,849,902 to Woolf et al., the entire disclosures of which are incorporated herein by reference.

Expression of a given miR gene can also be inhibited by an enzymatic nucleic acid. As used herein, an “enzymatic nucleic acid” refers to a nucleic acid comprising a substrate binding region that has complementarity to a contiguous nucleic acid sequence of an miR gene product, and which is able to specifically cleave the miR gene product. The enzymatic nucleic acid substrate binding region can be, for example, 50-100% complementary, 75-100% complementary, or 95-100% complementary to a contiguous nucleic acid sequence in a miR gene product. The enzymatic nucleic acids can also comprise modifications at the base, sugar, and/or phosphate groups. An exemplary enzymatic nucleic acid for use in the present methods is a ribozyme.

The enzymatic nucleic acids can be produced chemically or biologically, or can be expressed from a recombinant plasmid or viral vector, as described above for the isolated miR gene products. Exemplary methods for producing and testing dsRNA or siRNA molecules are described in Werner and Uhlenbeck (1995), Nucl. Acids Res. 23:2092-96; Hammann et al. (1999), Antisense and Nucleic Acid Drug Dev. 9:25-31; and U.S. Pat. No. 4,987,071 to Cech et al, the entire disclosures of which are incorporated herein by reference.

Administration of at least one miR gene product, or at least one compound for inhibiting miR expression, will inhibit the proliferation of cancer cells in a subject who has a cancer associated with a cancer-associated chromosomal feature. As used herein, to “inhibit the proliferation of a cancer cell” means to kill the cell, or permanently or temporarily arrest or slow the growth of the cell. Inhibition of cancer cell proliferation can be inferred if the number of such cells in the subject remains constant or decreases after administration of the miR gene products or miR gene expression-inhibiting compounds. An inhibition of cancer cell proliferation can also be inferred if the absolute number of such cells increases, but the rate of tumor growth decreases.

The number of cancer cells in a subject's body can be determined by direct measurement, or by estimation from the size of primary or metastatic tumor masses. For example, the number of cancer cells in a subject can be measured by immunohistological methods, flow cytometry, or other techniques designed to detect characteristic surface markers of cancer cells.

The size of a tumor mass can be ascertained by direct visual observation, or by diagnostic imaging methods, such as X-ray, magnetic resonance imaging, ultrasound, and scintigraphy. Diagnostic imaging methods used to ascertain size of the tumor mass can be employed with or without contrast agents, as is known in the art. The size of a tumor mass can also be ascertained by physical means, such as palpation of the tissue mass or measurement of the tissue mass with a measuring instrument, such as a caliper.

The miR gene products or miR gene expression-inhibiting compounds can be administered to a subject by any means suitable for delivering these compounds to cancer cells of the subject. For example, the miR gene products or miR expression inhibiting compounds can be administered by methods suitable to transfect cells of the subject with these compounds, or with nucleic acids comprising sequences encoding these compounds. In one embodiment, the cells are transfected with a plasmid or viral vector comprising sequences encoding at least one miR gene product or miR gene expression inhibiting compound.

Transfection methods for eukaryotic cells are well known in the art, and include, for example, direct injection of the nucleic acid into the nucleus or pronucleus of a cell; electroporation; liposome transfer or transfer mediated by lipophilic materials; receptor-mediated nucleic acid delivery, bioballistic or particle acceleration; calcium phosphate precipitation, and transfection mediated by viral vectors.

For example, cells can be transfected with a liposomal transfer compound, such as, DOTAP (N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethyl-ammonium methylsulfate, Boehringer-Mannheim) or an equivalent, such as LIPOFECTIN. The amount of nucleic acid used is not critical to the practice of the invention; acceptable results may be achieved with 0.1-100 micrograms of nucleic acid/105 cells. For example, a ratio of about 0.5 micrograms of plasmid vector in 3 micrograms of DOTAP per 105 cells can be used.

A miR gene product or miR gene expression inhibiting compound can also be administered to a subject by any suitable enteral or parenteral administration route. Suitable enteral administration routes for the present methods include, for example, oral, rectal, or intranasal delivery. Suitable parenteral administration routes include, for example, intravascular administration (for example, intravenous bolus injection, intravenous infusion, intra-arterial bolus injection, intra-arterial infusion and catheter instillation into the vasculature); peri- and intra-tissue injection (for example, peri-tumoral and intra-tumoral injection, intra-retinal injection, or subretinal injection); subcutaneous injection or deposition, including subcutaneous infusion (such as by osmotic pumps); direct application to the tissue of interest, for example by a catheter or other placement device (for example, a retinal pellet or a suppository or an implant comprising a porous, non-porous, or gelatinous material); and inhalation. Particularly suitable administration routes are injection, infusion and direct injection into the tumor.

In the present methods, a miR gene product or miR gene product expression inhibiting compound can be administered to the subject either as naked RNA, in combination with a delivery reagent, or as a nucleic acid (for example, a recombinant plasmid or viral vector) comprising sequences that express the miR gene product or expression inhibiting compound. Suitable delivery reagents include, for example, the Mirus Transit TKO lipophilic reagent; lipofectin; lipofectamine; cellfectin; polycations (for example, polylysine), and liposomes.

Recombinant plasmids and viral vectors comprising sequences that express the miR gene products or miR gene expression inhibiting compounds, and techniques for delivering such plasmids and vectors to cancer cells, are discussed herein.

In a particular embodiment, liposomes are used to deliver a miR gene product or miR gene expression-inhibiting compound (or nucleic acids comprising sequences encoding them) to a subject. Liposomes can also increase the blood half-life of the gene products or nucleic acids. Suitable liposomes for use in the invention can be formed from standard vesicle-forming lipids, which generally include neutral or negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of factors, such as the desired liposome size and half-life of the liposomes in the blood stream. A variety of methods are known for preparing liposomes, for example, as described in Szoka et al. (1980), Ann. Rev. Biophys. Bioeng. 9:467; and U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369, the entire disclosures of which are incorporated herein by reference.

The liposomes for use in the present methods can comprise a ligand molecule that targets the liposome to cancer cells. Ligands which bind to receptors prevalent in cancer cells, such as monoclonal antibodies that bind to tumor cell antigens, are preferred.

The liposomes for use in the present methods can also be modified so as to avoid clearance by the mononuclear macrophage system (“MMS”) and reticuloendothelial system (“RES”). Such modified liposomes have opsonization-inhibition moieties on the surface or incorporated into the liposome structure. In a particularly preferred embodiment, a liposome of the invention can comprise both opsonization-inhibition moieties and a ligand.

Opsonization-inhibiting moieties for use in preparing the liposomes of the invention are typically large hydrophilic polymers that are bound to the liposome membrane. As used herein, an opsonization inhibiting moiety is “bound” to a liposome membrane when it is chemically or physically attached to the membrane, for example, by the intercalation of a lipid-soluble anchor into the membrane itself, or by binding directly to active groups of membrane lipids. These opsonization-inhibiting hydrophilic polymers form a protective surface layer that significantly decreases the uptake of the liposomes by the MMS and RES; for example, as described in U.S. Pat. No. 4,920,016, the entire disclosure of which is incorporated herein by reference.

Opsonization inhibiting moieties suitable for modifying liposomes are preferably water-soluble polymers with a number-average molecular weight from about 500 to about 40,000 daltons, and more preferably from about 2,000 to about 20,000 daltons. Such polymers include polyethylene glycol (PEG) or polypropylene glycol (PPG) derivatives; for example, methoxy PEG or PPG, and PEG or PPG stearate; synthetic polymers, such as polyacrylamide or poly N-vinyl pyrrolidone; linear, branched, or dendrimeric polyamidoamines; polyacrylic acids; polyalcohols, for example, polyvinylalcohol and polyxylitol to which carboxylic or amino groups are chemically linked, as well as gangliosides, such as ganglioside GM1. Copolymers of PEG, methoxy PEG, or methoxy PPG, or derivatives thereof, are also suitable. In addition, the opsonization inhibiting polymer can be a block copolymer of PEG and either a polyamino acid, polysaccharide, polyamidoamine, polyethyleneamine, or polynucleotide. The opsonization inhibiting polymers can also be natural polysaccharides containing amino acids or carboxylic acids, for example, galacturonic acid, glucuronic acid, mannuronic acid, hyaluronic acid, pectic acid, neuraminic acid, alginic acid, carrageenan; aminated polysaccharides or oligosaccharides (linear or branched); or carboxylated polysaccharides or oligosaccharides, for example, reacted with derivatives of carbonic acids with resultant linking of carboxylic groups. Preferably, the opsonization-inhibiting moiety is a PEG, PPG, or derivatives thereof. Liposomes modified with PEG or PEG-derivatives are sometimes called “PEGylated liposomes.”

The opsonization inhibiting moiety can be bound to the liposome membrane by any one of numerous well-known techniques. For example, an N-hydroxysuccinimide ester of PEG can be bound to a phosphatidyl-ethanolamine lipid-soluble anchor, and then bound to a membrane. Similarly, a dextran polymer can be derivatized with a stearylamine lipid-soluble anchor via reductive amination using Na(CN)BH3 and a solvent mixture, such as tetrahydrofuran and water in a 30:12 ratio at 60° C.

Liposomes modified with opsonization-inhibition moieties remain in the circulation much longer than unmodified liposomes. For this reason, such liposomes are sometimes called “stealth” liposomes. Stealth liposomes are known to accumulate in tissues fed by porous or “leaky” microvasculature. Thus, tissue characterized by such microvasculature defects, for example solid tumors, will efficiently accumulate these liposomes; see Gabizon, et al. (1988), Proc. Natl. Acad. Sci., U.S.A., 18:6949-53. In addition, the reduced uptake by the RES lowers the toxicity of stealth liposomes by preventing significant accumulation of the liposomes in the liver and spleen. Thus, liposomes that are modified with opsonization-inhibition moieties are particularly suited to deliver the miR gene products or miR gene expression inhibition compounds (or nucleic acids comprising sequences encoding them) to tumor cells.

The miR gene products or miR gene expression inhibition compounds can be formulated as pharmaceutical compositions, sometimes called “medicaments,” prior to administering them to a subject, according to techniques known in the art. Accordingly, the invention encompasses pharmaceutical compositions for treating breast cancer. In one embodiment, the pharmaceutical compositions comprise at least one isolated miR gene product and a pharmaceutically-acceptable carrier. In a particular embodiment, the at least one miR gene product corresponds to a miR gene product that has a decreased level of expression in breast cancer cells relative to suitable control cells. In certain embodiments the isolated miR gene product is selected from the group consisting of miR-145, miR-10b, miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, miR-101-1, miR-143 and combinations thereof.

In other embodiments, the pharmaceutical compositions of the invention comprise at least one miR expression inhibition compound. In a particular embodiment, the at least one miR gene expression inhibition compound is specific for a miR gene whose expression is greater in breast cancer cells than control cells. In certain embodiments, the miR gene expression inhibition compound is specific for one or more miR gene products selected from the group consisting of miR-21, miR-155, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-213, let-7i (let-7d-v2), miR-122a, miR-128b, miR-136, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210, miR-213 and combinations thereof.

Pharmaceutical compositions of the present invention are characterized as being at least sterile and pyrogen-free. As used herein, “pharmaceutical formulations” include formulations for human and veterinary use. Methods for preparing pharmaceutical compositions of the invention are within the skill in the art, for example as described in Remington's Pharmaceutical Science, 17th ed., Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated herein by reference.

The present pharmaceutical formulations comprise at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them) (for example, 0.1 to 90% by weight), or a physiologically acceptable salt thereof, mixed with a pharmaceutically-acceptable carrier. The pharmaceutical formulations of the invention can also comprise at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them) which are encapsulated by liposomes and a pharmaceutically-acceptable carrier. In one embodiment, the pharmaceutical compositions comprise a miR gene or gene product that is not miR-15, miR-16, miR-143 and/or miR-145.

Especially suitable pharmaceutically-acceptable carriers are water, buffered water, normal saline, 0.4% saline, 0.3% glycine, hyaluronic acid and the like.

In a particular embodiment, the pharmaceutical compositions of the invention comprise at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them) which is resistant to degradation by nucleases. One skilled in the art can readily synthesize nucleic acids which are nuclease resistant, for example by incorporating one or more ribonucleotides that are modified at the 2′-position into the miR gene products. Suitable 2′-modified ribonucleotides include those modified at the 2′-position with fluoro, amino, alkyl, alkoxy, and O-allyl.

Pharmaceutical compositions of the invention can also comprise conventional pharmaceutical excipients and/or additives. Suitable pharmaceutical excipients include stabilizers, antioxidants, osmolality adjusting agents, buffers, and pH adjusting agents. Suitable additives include, for example, physiologically biocompatible buffers (for example, tromethamine hydrochloride), additions of chelants (such as, for example, DTPA or DTPA-bisamide) or calcium chelate complexes (such as, for example, calcium DTPA, CaNaDTPA-bisamide), or, optionally, additions of calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate). Pharmaceutical compositions of the invention can be packaged for use in liquid form, or can be lyophilized.

For solid pharmaceutical compositions of the invention, conventional nontoxic solid pharmaceutically-acceptable carriers can be used; for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.

For example, a solid pharmaceutical composition for oral administration can comprise any of the carriers and excipients listed above and 10-95%, preferably 25%-75%, of the at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them). A pharmaceutical composition for aerosol (inhalational) administration can comprise 0.01-20% by weight, preferably 1%-10% by weight, of the at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them) encapsulated in a liposome as described above, and a propellant. A carrier can also be included as desired; for example, lecithin for intranasal delivery.

The invention also encompasses methods of identifying an anti-breast cancer agent, comprising providing a test agent to a cell and measuring the level of at least one miR gene product in the cell. In one embodiment, the method comprises providing a test agent to a cell and measuring the level of at least one miR gene product associated with decreased expression levels in breast cancer cells. An increase in the level of the miR gene product in the cell, relative to a suitable control cell, is indicative of the test agent being an anti-breast cancer agent. In a particular embodiment, at least one miR gene product associated with decreased expression levels in breast cancer cells is selected from the group consisting of miR-145, miR-10b, miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, miR-101-1, miR-143 and combinations thereof.

In other embodiments the method comprises providing a test agent to a cell and measuring the level of at least one miR gene product associated with increased expression levels in breast cancer cells. A decrease in the level of the miR gene product in the cell, relative to a suitable control cell, is indicative of the test agent being an anti-breast cancer agent. In a particular embodiment, at least one miR gene product associated with increased expression levels in breast cancer cells is selected from the group consisting of miR-21, miR-155, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-213, let-7i (let-7d-v2), miR-122a, miR-128b, miR-136, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210, miR-213 and combinations thereof.

Suitable agents include, but are not limited to drugs (for example, small molecules, peptides), and biological macromolecules (for example, proteins, nucleic acids). The agent can be produced recombinantly, synthetically, or it may be isolated (i.e., purified) from a natural source. Various methods for providing such agents to a cell (for example, transfection) are well known in the art, and several of such methods are described hereinabove. Methods for detecting the expression of at least one miR gene product (for example, Northern blotting, in situ hybridization, RT-PCR, expression profiling) are also well known in the art. Several of these methods are also described hereinabove.

The invention will now be illustrated by the following non-limiting examples.

Example 1 Identification of a microRNA Expression Signature that Discriminates Breast Cancer Tissues from Normal Tissues

Materials and Methods

Breast Cancer Samples and Cell Lines.

RNAs from primary tumors were obtained from 76 samples collected at the University of Ferrara (Italy), Istituto Nazionale dei Tumori, Milano (Italy) and Thomas Jefferson University (Philadelphia, Pa.). Clinico-pathological information was available for 58 tumor samples. RNA from normal samples consisted of 6 pools of RNA from 5 normal breast tissues each, as well as RNA from 4 additional single breast tissues. Breast cancer RNAs were also obtained from the following cell lines: Hs578-T, MCF7, T47D, BT20, SK-BR-3, HBL100, HCC2218, MDA-MB-175, MDA-MB-231, MDA-MB-361, MDA-MB-435, MDA-MB-436, MDA-MB-453 and MDAMB-468.

miRNA Microarray.

Total RNA isolation was performed with Trizol Reagent (Invitrogen) according to the manufacturer's instructions. RNA labeling and hybridization on microRNA microarray chips was performed as previously described (Liu, C.-G., et al., Proc. Natl. Acad. Sci. U.S.A. 101:9740-9744 (2004)). Briefly, 5 μg of RNA from each sample was labeled with biotin during reverse transcription using random hexamers. Hybridization was carried out on a miRNA microarray chip (KCl version 1.0), which contains 368 probes, including 245 human and mouse miRNA genes, in triplicate. Hybridization signals were detected by binding of biotin to a Streptavidin-Alexa647 conjugate using a Perkin-Elmer ScanArray XL5K. Scanner images were quantified by the Quantarray software (Perkin Elmer).

Statistical and bioinformatic analysis of microarray data. Raw data were normalized and analyzed using the GeneSpring® software, version 7.2 (SiliconGenetics, Redwood City, Calif.). Expression data were median centered. Statistical comparisons were performed by ANOVA (Analysis of Variance), using the Benjamini and Hochberg correction for reduction of false positives. Prognostic miRNAs for tumor or normal class prediction were determined using both the PAM software (Prediction Analysis of Microarrays) (Tibshirani, R., et al. Proc. Natl. Acad. Sci. U.S.A. 99:6567-6572 (2002)) and the Support Vector Machine (Furey, T. S., et al. Bioinformatics 16: 906-914 (2000)) software. Both algorithms were used for Cross-validation and Test-set prediction. All data were submitted using MIAMExpress to the Array Express database.

Northern Blotting.

Northern blot analysis was performed as previously described (Calin, G. A., et al., Proc. Natl. Acad. Sci. U.S.A. 99:15524-29 (2002)). RNA samples (10 μg each) were electrophoresed on 15% acrylamide, 7 M urea Criterion pre-casted gels (Bio-Rad) and transferred onto Hybond-N+ membrane (Amersham Pharmacia Biotech). The hybridization was performed at 37° C. in 7% sodium dodecyl sulfate (SDS)/0.2M Na2PO4 (pH 7.0) for 16 hours. Membranes were washed twice at 42° C. with 2× standard saline phosphate (0.18 M NaCl/10 mM phosphate, pH 7.4), supplemented with 1 mM EDTA (SSPE) and 0.1% SDS, and twice with 0.5×SSPE/0.1% SDS. Oligonucleotide probes were complementary to the sequence of the corresponding mature microRNA (see Sanger miR Registry): miR-21 5′-TCA ACA TCA GTC TGA TAA GCT A-3′ (SEQ ID NO:287); miR-125b1: 5′-TCA CAA GTT AGG GTC TCA GGG A-3′ (SEQ ID NO:288); miR-145: 5′-AAG GGA TTC CTG GGA AAA CTG GAC-3′ (SEQ ID NO:289). An oligonucleotide that was complementary to the U6 RNA (5′-GCA GGG GCC ATG CTA ATC TTC TCT GTA TCG-3′ (SEQ ID NO:290)) was used for normalizing expression levels. 200 μg of each probe was end labeled with 100 mCi [gamma-32P]-ATP using a polynucleotide kinase (Roche). Northern Blots were stripped in a boiling 0.1% SDS solution for 10 minutes before re-hybridization.

Results

A microRNA microarray (Liu, C.-G., et al., Proc. Natl. Acad. Sci. U.S.A. 101:9740-9744 (2004)) was used to generate microRNA expression profiles for 10 normal and 76 neoplastic breast tissues. Each tumor sample was derived from a single specimen, while 6 of the 10 normal samples consisted of pools of RNA made from five different normal breast tissues. Hence, 34 normal breast samples were actually examined in the study.

To identify miRNAs that were differentially-expressed between normal and tumor samples, and, therefore, can be used to distinguish normal from cancerous breast tissues, analyses of variance and class prediction statistical tools were utilized. Results of the ANOVA analysis on normalized data generated a profile of differentially-expressed miRNAs (p<0.05) between normal and cancerous breast tissues (Table 2). Cluster analysis, based on differentially-expressed miRNA, generated a tree having a clear distinction between normal and cancer tissues (FIG. 1A).

To accurately identify a set of predictive miRNAs capable of differentiating normal from breast cancer tissues, we used Support Vector Machine (GeneSpring software) and PAM (Prediction Analysis of Micro arrays). Results from the two class prediction analyses largely overlapped (Table 3 and FIG. 1B). Among the miRNAs listed in Table 3, 11 of 15 have an ANOVA p-value of less than 0.05. To confirm the results obtained by microarray analysis, we performed Northern blot analysis to assess expression levels for a subset of microRNAs, namely, mir-125b, mir-145 and mir-21, that were differentially-expressed in normal and cancerous breast tissues. Northern blot analysis confirmed results obtained by microarray analysis. In many cases, expression differences appeared stronger than those anticipated by the microarray studies (FIG. 1C).

TABLE 2 miRNAs differentially-expressed between breast carcinoma and normal breast tissue. Breast Cancer Normal Breast Median Range Median Range P-value Normalized Min Max Normalized Min Max let-7a-2 1.94E−02 1.67 0.96 - 6.21 2.30 1.34 - 5.00 let-7a-3 4.19E−02 1.26 0.81 - 3.79 1.58 1.02 - 2.91 let-7d (=7d-v1) 4.61E−03 0.90 0.59 - 1.54 1.01 0.83 - 1.25 let-7f-2 6.57E−03 0.84 0.51 - 1.58 0.92 0.76 - 1.03 let-7i (=let-7d-v2) 3.38E−02 2.05 1.02 - 7.49 1.53 1.01 - 3.47 mir-009-1 (mir-131-1) 9.12E−03 1.36 0.69 - 4.16 1.01 0.61 - 2.44 mir-010b 4.49E−02 1.11 0.69 - 4.79 1.70 0.96 - 6.32 mir-021 4.67E−03 1.67 0.66 - 26.43 1.08 0.80 - 2.31 mir-034 (mir-170) 1.06E−02 1.67 0.70 - 6.40 1.09 0.65 - 3.17 mir-101-1 4.15E−03 0.83 0.52 - 1.26 0.90 0.77 - 1.05 mir-122a 3.43E−03 2.21 0.93 - 8.08 1.48 1.06 - 3.67 mir-125a 3.28E−03 1.20 0.69 - 2.36 1.73 1.21 - 3.34 mir-125b-1 2.65E−02 1.30 0.55 - 8.68 2.87 1.45 - 18.38 mir-125b-2 2.33E−02 1.26 0.69 - 8.28 2.63 1.40 - 18.78 mir-126b 1.60E−02 1.12 0.68 - 7.34 1.02 0.89 - 1.27 mir-136 2.42E−03 1.32 0.74 - 10.26 1.05 0.76 - 1.47 mir-143 7.11E−03 0.87 0.68 - 1.33 0.98 0.81 - 1.17 mir-145 4.02E−03 1.52 0.92 - 8.46 3.61 1.85 - 14.45 mir-149 2.75E−02 1.11 0.53 - 1.73 1.03 0.83 - 1.22 mir-155(BIC) 1.24E−03 1.75 0.95 - 11.45 1.37 1.11 - 1.88 mir-191 4.26E−02 5.17 1.03 - 37.81 3.12 1.45 - 14.56 mir-196-1 1.07E−02 1.20 0.57 - 3.95 0.95 0.66 - 1.75 mir-196-2 1.16E−03 1.46 0.57 - 5.55 1.04 0.79 - 1.80 mir-202 1.25E−02 1.05 0.71 - 2.03 0.89 0.65 - 1.20 mir-203 4.06E−07 1.12 0.50 - 5.89 0.86 0.71 - 1.04 mir-204 2.15E−03 0.78 0.46 - 1.04 0.89 0.72 - 1.08 mir-206 1.42E−02 2.55 1.22 - 8.42 1.95 1.34 - 3.22 mir-210 6.40E−13 1.60 0.98 - 12.13 1.12 0.97 - 1.29 mir-213 1.08E−02 3.72 1.42 - 40.83 2.47 1.35 - 5.91

TABLE 3 Normal and tumor breast tissues class predictor microRNAs Median SVM expression ANOVAa prediction PAM scorec Chromos miRNA name Cancer Normal Probability strengthb Cancer Normal map mir-009-1 1.36 1.01 0.0091 8.05 0.011 −0.102 1q22 mir-010b 1.11 1.70 0.0449 8.70 −0.032 0.299 2q31 mir-021 1.67 1.08 0.0047 10.20 0.025 −0.235 17q23.2 mir-034 1.67 1.09 0.0106 8.05 0.011 −0.106 1p36.22 mir-102 (mir-29b) 1.36 1.14 >0.10 8.92 0.000 −0.004 1q32.2-32.3 mir-123 (mir-126) 0.92 1.13 0.0940 9.13 −0.015 0.138 9q34 mir-125a 1.20 1.73 0.0033 8.99 −0.040 0.381 19q13.4 mir-125b-1 1.30 2.87 0.0265 14.78 −0.096 0.915 11q24.1 mir-125b-2 1.26 2.63 0.0233 17.62 −0.106 1.006 21q11.2 mir-140-as 0.93 1.10 0.0695 11.01 −0.005 0.050 16q22.1 mir-145 1.52 3.61 0.0040 12.93 −0.158 1.502 5q32-33 mir-155(BIC) 1.75 1.37 0.0012 10.92 0.003 −0.030 21q21 mir-194 0.96 1.09 >0.10 11.12 −0.025 0.234 1q41 mir-204 0.78 0.89 0.0022 8.10 −0.015 0.144 9q21.1 mir-213 3.72 2.47 0.0108 9.44 0.023 −0.220 1q31.3-q32.1 aAnalysis of Variance (Welch t-test in Genespring software package) as calculated in Table 2. bSupport Vector Machine prediction analysis tool (from Genespring 7.2 software package). Prediction strengths are calculated as negative natural log of the probability to predict the observed number of samples, in one of the two classes, by chance. The higher is the score, the best is the prediction strength. cCentroid scores for the two classes of the Prediction Analysis of Microarrays (Tibshirani, R., et al. Proc. Natl. Acad. Sci. U.S.A. 99: 6567-6572 (2002)).

Of the 29 miRNAs whose expression is significantly (p<0.05) deregulated according to the microarray analysis, a set of 15 miRNAs were able to correctly predict the nature of the sample analyzed (i.e., normal vs. tumor) with 100% accuracy. Among the differentially-expressed miRNAs, miR-10b, miR-125b, miR145, miR-21 and miR-155 were the most consistently deregulated miRNAs in breast cancer samples. Three of these, namely, miR-10b, miR-125b and miR-145, were down-regulated, while the remaining two, miR-21 and miR-155, were up-regulated, suggesting that they might act as tumor suppressor genes or oncogenes, respectively.

Example 2 Determination of Putative Gene Targets of miRNAs that are Deregulated in Breast Cancer Tissues

At present, the lack of knowledge about bona fide miRNA gene targets hampers a full understanding of which biological functions are deregulated in cancers characterized by aberrant miRNA expression. To identify putative targets of the most significantly de-regulated miRNAs from our study: miR-10b, miR125b, miR-145, miR-21 and miR-155 (see Example 1), we utilized multiple computational approaches. In particular, the analysis was performed using three algorithms, miRanda, TargetScan and PicTar, which are used to predict human miRNA gene targets (Enright, A. J., et al. Genome Biol. 5:R1 (2003); Lewis, B. P. et al., Cell 115:787-798 (2003); Krek, A., et al., Nat. Genet. 37:495-500 (2005)). The results obtained using each of the three algorithms were cross-referenced with one another to validate putative targets, and only targets that were identified by at least 2 of the 3 algorithms were considered. Results of this analysis are presented in Table 4.

Several genes with potential oncogenic functions were identified as putative targets of miRNAs that are down-regulated in breast cancer samples. Notably, oncogenes were identified as targets of miR-10b (for example, FLT1, the v-crk homolog, the growth factor BDNF and the transducing factor SHC1), miR-125b (for example, YES, ETS1, TEL, AKT3, the growth factor receptor FGFR2 and members of the mitogen-activated signal transduction pathway VTS58635, MAP3K10, MAP3K11, MAPK14), and miR-145 (for example, MYCN, FOS, YES and FLI1, integration site of Friend leukemia virus, cell cycle promoters, such as cyclins D2 and L1, MAPK transduction proteins, such as MAP3K3 and MAP4K4). The proto-oncogene, YES, and the core-binding transcription factor, CBFB, were determined to be potential targets of both miR-125 and miR-145.

Consistent with these findings, multiple tumor suppressor genes were identified as targets of miR-21 and miR-155, miRNAs that are up-regulated in breast cancer cells. For miR-21, the TGFB gene was predicted as target by all three methods. For miR-155, potential targets included the tumor suppressor genes, SOCS1 and APC, and the kinase, WEE1, which blocks the activity of Cdc2 and prevents entry into mitosis. The hypoxia inducible factor, HIF1A, was also a predicted target of miR-155. Notably, the tripartite motif-containing protein TRIM2, the proto-oncogene, SKI, and the RAS homologs, RAB6A and RAB6C, were found as potential targets of both miR-21 and miR-155.

TABLE 4 Putative gene targets of differentially-expressed miRNA identified by at least two prediction methods Prediction miRNA Genbank Gene Symbol Gene Name algorithm Gene Ontology condensed miR-10b AL117516 38596 strand-exchange protein 1 P + T exonuclease activity|nucleus miR-10b NM_004915 ABCG1 ATP-binding cassette, sub- P + T ATP binding|ATPase family G (WHITE), member 1 activity|ATPase activity, coupled to transmembrane movement of substances|L-tryptophan transporter activity|cholesterol homeostasis|cholesterol metabolism|detection of hormone stimulus|integral to plasma membrane|lipid transport|membrane|membrane fraction|permease activity|protein dimerization activity|purine nucleotide transporter activity|response to organic substance miR-10b NM_001148 ANK2 ankyrin 2, neuronal P + T actin cytoskeleton|membrane|metabolism| oxidoreductase activity|protein binding|signal transduction|structural constituent of cytoskeleton miR-10b NM_020987 ANK3 ankyrin 3, node of Ranvier P + T Golgi apparatus|cytoskeletal (ankyrin G) anchoring|cytoskeleton|cytoskeleton| endoplasmic reticulum|protein binding|protein targeting|signal transduction|structural constituent of cytoskeleton miR-10b NM_016376 ANKHZN ANKHZN protein P + T endocytosis|endosome membrane|membrane|protein binding|zinc ion binding miR-10b NM_006380 APPBP2 amyloid beta precursor P + T binding|cytoplasm|intracellular protein (cytoplasmic tail) protein binding protein 2 transport|membrane|microtubule associated complex|microtubule motor activity|nucleus miR-10b NM_006321 ARIH2 ariadne homolog 2 P + T development|nucleic acid (Drosophila) binding|nucleus|protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-10b NM_001668 ARNT aryl hydrocarbon receptor P + T aryl hydrocarbon receptor nuclear nuclear translocator translocator activity|nucleus|nucleus|protein- nucleus import, translocation|receptor activity|regulation of transcription, DNA-dependent|signal transducer activity|signal transduction|transcription coactivator activity|transcription factor activity|transcription factor activity miR-10b AI829840 ASXL1 ESTs, Weakly similar to P + T nucleus|regulation of transcription, SFRB_HUMAN Splicing DNA-dependent|transcription factor arginine/serine-rich 11 (Arginine-rich 54 kDa nuclear protein) (P54) [H. sapiens] miR-10b NM_021813 BACH2 BTB and CNC homology 1, P + T DNA binding|nucleus|protein basic leucine zipper binding|regulation of transcription, transcription factor 2 DNA-dependent|transcription miR-10b NM_013450 BAZ2B bromodomain adjacent to P + T DNA binding|nucleus|regulation of zinc finger domain, 2B transcription, DNA- dependent|transcription miR-10b NM_001706 BCL6 B-cell CLL/lymphoma 6 P + T inflammatory response|mediator (zinc finger protein 51) complex|negative regulation of transcription from RNA polymerase II promoter|nucleus|positive regulation of cell proliferation|protein binding|regulation of transcription, DNA- dependent|transcription|transcription factor activity|zinc ion binding miR-10b NM_001709 BDNF brain-derived neurotrophic P + T growth factor activity|growth factor factor activity|neurogenesis miR-10b NM_006624 BS69 adenovirus 5 E1A binding P + T DNA binding|cell cycle|cell protein proliferation|negative regulation of cell cycle|negative regulation of transcription from RNA polymerase II promoter|nucleus|regulation of transcription, DNA- dependent|transcription miR-10b AF101784 BTRC beta-transducin repeat P + T Wnt receptor signaling containing pathway|endoplasmic reticulum|ligase activity|signal transduction|ubiquitin conjugating enzyme activity|ubiquitin cycle|ubiquitin-dependent protein catabolism miR-10b NM_005808 C3orf8 HYA22 protein P + T biological_process unknown|molecular_function unknown|nucleus miR-10b BF111268 CAMK2G calcium/calmodulin- P + T ATP binding|ATP binding|calcium- dependent protein kinase and calmodulin-dependent protein (CaM kinase) II gamma kinase activity|calcium-dependent protein serine/threonine phosphatase activity|calmodulin binding|cellular_component unknown|insulin secretion|kinase activity|protein amino acid phosphorylation|protein amino acid phosphorylation|protein serine/threonine kinase activity|protein-tyrosine kinase activity|signal transduction|transferase activity miR-10b NM_020184 CNNM4 cyclin M4 P + T miR-10b NM_022730 COPS7B COP9 constitutive P + T signalosome complex photomorphogenic homolog subunit 7B (Arabidopsis) miR-10b NM_016823 CRK v-crk sarcoma virus CT10 P + T SH3/SH2 adaptor activity|actin oncogene homolog (avian) cytoskeleton organization and biogenesis|cell motility|cytoplasm|intracellular signaling cascade|nucleus|regulation of transcription from RNA polymerase II promoter miR-10b NM_020248 CTNNBIP1 catenin, beta interacting P + T Wnt receptor signaling pathway|beta- protein 1 catenin binding|cell proliferation|development|nucleus|regulation of transcription, DNA- dependent|signal transduction miR-10b NM_018959 DAZAP1 DAZ associated protein 1 P + T RNA binding|cell differentiation|nucleotide binding|nucleus|spermatogenesis miR-10b AL136828 DKFZP434K0427 hypothetical protein P + T cation transport|cation transporter DKFZp434K0427 activity miR-10b R20763 DKFZp547J036 ELAV (embryonic lethal, P + T abnormal vision, Drosophila)-like 3 (Hu antigen C) miR-10b AF009204 DLGAP2 discs, large (Drosophila) P + T cell-cell signaling|membrane|nerve- homolog-associated protein 2 nerve synaptic transmission|neurofilament|protein binding miR-10b NM_001949 E2F3 E2F transcription factor 3 P + T nucleus|protein binding|regulation of cell cycle|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcription factor complex|transcription initiation from RNA polymerase II promoter miR-10b NM_022659 EBF2 early B-cell factor 2 P + T DNA binding|development|nucleus|regulation of transcription, DNA- dependent|transcription miR-10b NM_004432 ELAVL2 ELAV (embryonic lethal, P + T RNA binding|mRNA 3′-UTR abnormal vision, binding|nucleotide binding|regulation Drosophila)-like 2 (Hu of transcription, DNA-dependent antigen B) miR-10b NM_001420 ELAVL3 ELAV (embryonic lethal, P + T RNA binding|cell abnormal vision, differentiation|mRNA 3′-UTR Drosophila)-like 3 (Hu binding|neurogenesis|nucleotide antigen C) binding miR-10b NM_004438 EPHA4 EphA4 P + T ATP binding|ephrin receptor activity|integral to plasma membrane|membrane|protein amino acid phosphorylation|receptor activity|signal transduction|transferase activity|transmembrane receptor protein tyrosine kinase signaling pathway miR-10b AL035703 EPHA8; EEK; EphA8 P + T HEK3; Hek3; KIAA1459 miR-10b NM_004468 FHL3 four and a half LIM P + T muscle development|zinc ion binding domains 3 miR-10b NM_024679 FLJ11939 hypothetical protein P + T FLJ11939 miR-10b AI742838 FLJ32122 hypothetical protein P + T GTP binding|GTPase FLJ32122 binding|guanyl-nucleotide exchange factor activity miR-10b AL040935 FLJ33957 hypothetical protein P + T protein binding FLJ33957 miR-10b AA058828 FLT1 ESTs P + T ATP binding|angiogenesis|cell differentiation|extracellular space|integral to plasma membrane|membrane|positive regulation of cell proliferation|pregnancy|protein amino acid phosphorylation|receptor activity|transferase activity|transmembrane receptor protein tyrosine kinase signaling pathway|vascular endothelial growth factor receptor activity miR-10b NM_004860 FXR2 fragile X mental retardation, P + T RNA binding|cytoplasm|cytosolic autosomal homolog 2 large ribosomal subunit (sensu Eukaryota)|nucleus miR-10b NM_020474 GALNT1 UDP-N-acetyl-alpha-D- P + T Golgi apparatus|O-linked galactosamine:polypeptide glycosylation|integral to N-acetylgalactosaminyl- membrane|manganese ion transferase 1 binding|polypeptide N- (GalNAc-T1) acetylgalactosaminyltransferase activity|sugar binding|transferase activity, transferring glycosyl groups miR-10b D87811 GATA6 GATA binding protein 6 P + T muscle development|nucleus|positive regulation of transcription|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcriptional activator activity|zinc ion binding miR-10b NM_000840 GRM3 glutamate receptor, P + T G-protein coupled receptor protein metabotropic 3 signaling pathway|integral to plasma membrane|membrane|metabotropic glutamate, GABA-B-like receptor activity|negative regulation of adenylate cyclase activity|receptor activity|signal transduction|synaptic transmission miR-10b NM_005316 GTF2H1 general transcription factor P + T DNA repair|[RNA-polymerase]- IIH, polypeptide 1, 62 kDa subunit kinase activity|general RNA polymerase II transcription factor activity|nucleus|regulation of cyclin dependent protein kinase activity|regulation of transcription, DNA- dependent|transcription|transcription factor TFIIH complex|transcription from RNA polymerase II promoter miR-10b AF232772 HAS3 hyaluronan synthase 3 P + T carbohydrate metabolism|hyaluronan synthase activity|integral to plasma membrane|transferase activity, transferring glycosyl groups miR-10b AL023584 HIVEP2 human immunodeficiency P + T virus type I enhancer binding protein 2 miR-10b S79910 HOXA1 homeo box A1 P + T RNA polymerase II transcription factor activity|development|nucleus|regulation of transcription, DNA- dependent|transcription factor activity miR-10b NM_030661 HOXA3 homeo box A3 P + T development|nucleus|regulation of transcription, DNA- dependent|transcription factor activity miR-10b AW299531 HOXD10 homeo box D10 P + T RNA polymerase II transcription factor activity|development|nucleus|regulation of transcription, DNA- dependent|transcription factor activity miR-10b BF031714 HYA22 HYA22 protein P + T miR-10b NM_001546 ID4 inhibitor of DNA binding 4, P + T nucleus|regulation of transcription dominant negative helix- from RNA polymerase II loop-helix protein promoter|transcription corepressor activity miR-10b NM_014333 IGSF4 immunoglobulin P + T superfamily, member 4 miR-10b NM_014271 IL1RAPL1 interleukin 1 receptor P + T integral to membrane|learning and/or accessory protein-like 1 memory|membrane|signal transduction|transmembrane receptor activity miR-10b D87450 KIAA0261 KIAA0261 protein P + T miR-10b AL117518 KIAA0978 KIAA0978 protein P + T nucleus|regulation of transcription, DNA-dependent|transcription miR-10b AK025960 KIAA1255 KIAA1255 protein P + T endocytosis|endosome membrane|membrane|protein binding|zinc ion binding miR-10b AB037797 KIAA1376 KIAA1376 protein P + T miR-10b NM_004795 KL klotho P + T beta-glucosidase activity|carbohydrate metabolism|extracellular space|glucosidase activity|integral to membrane|integral to plasma membrane|membrane fraction|signal transducer activity|soluble fraction miR-10b NM_015995 KLF13 Kruppel-like factor 13 P + T DNA binding|RNA polymerase II transcription factor activity|nucleus|regulation of transcription, DNA- dependent|transcription|transcription from RNA polymerase II promoter|zinc ion binding miR-10b NM_004235 KLF4 Kruppel-like factor 4 (gut) P + T mesodermal cell fate determination|negative regulation of cell proliferation|negative regulation of transcription, DNA- dependent|negative regulation of transcription, DNA- dependent|nucleic acid binding|nucleus|transcription|transcription factor activity|transcription factor activity|transcriptional activator activity|transcriptional activator activity|transcriptional repressor activity|transcriptional repressor activity|zinc ion binding|zinc ion binding miR-10b AW511293 LOC144455 hypothetical protein P + T regulation of cell cycle|regulation of BC016658 transcription, DNA- dependent|transcription factor activity|transcription factor complex miR-10b NM_014921 LPHN1 lectomedin-2 P + T G-protein coupled receptor activity|integral to membrane|latrotoxin receptor activity|membrane|neuropeptide signaling pathway|receptor activity|signal transduction|sugar binding miR-10b NM_012325 MAPRE1 microtubule-associated P + T cell protein, RP/EB family, proliferation|cytokinesis|microtubule member 1 binding|mitosis|protein C-terminus binding|regulation of cell cycle miR-10b AA824369 MGC4643 hypothetical protein P + T Wnt receptor signaling MGC4643 pathway|endoplasmic reticulum|ligase activity|signal transduction|ubiquitin conjugating enzyme activity|ubiquitin cycle|ubiquitin-dependent protein catabolism miR-10b NM_021090 MTMR3 myotubularin related protein 3 P + T cytoplasm|hydrolase activity|inositol or phosphatidylinositol phosphatase activity|membrane|membrane fraction|phospholipid dephosphorylation|protein amino acid dephosphorylation|protein serine/threonine phosphatase activity|protein tyrosine phosphatase activity|protein tyrosine/serine/threonine phosphatase activity|zinc ion binding miR-10b AI498126 NAC1 transcriptional repressor P + T protein binding NAC1 miR-10b AF128458 NCOA6 nuclear receptor coactivator 6 P + T DNA recombination|DNA repair|DNA replication|brain development|chromatin binding|embryonic development (sensu Mammalia)|estrogen receptor binding|estrogen receptor signaling pathway|glucocorticoid receptor signaling pathway|heart development|ligand-dependent nuclear receptor transcription coactivator activity|myeloid blood cell differentiation|nucleus|nucleus|positive regulation of transcription from RNA polymerase II promoter|protein binding|regulation of transcription, DNA-dependent|response to hormone stimulus|retinoid X receptor binding|thyroid hormone receptor binding|transcription|transcription factor complex|transcription initiation from RNA polymerase II promoter|transcriptional activator activity miR-10b NM_006312 NCOR2 nuclear receptor corepressor 2 P + T DNA binding|nucleus|regulation of transcription, DNA- dependent|transcription corepressor activity miR-10b NM_006599 NFAT5 nuclear factor of activated P + T RNA polymerase II transcription T-cells 5, tonicity- factor responsive activity|excretion|nucleus|regulation of transcription, DNA- dependent|signal transduction|transcription factor activity|transcription from RNA polymerase II promoter miR-10b NM_006981 NR4A3 nuclear receptor subfamily M + P + T binding|nucleus|nucleus|regulation of 4, group A, member 3 transcription, DNA- dependent|steroid hormone receptor activity|steroid hormone receptor activity|thyroid hormone receptor activity|transcription|transcription factor activity miR-10b NM_003822 NR5A2 nuclear receptor subfamily P + T RNA polymerase II transcription 5, group A, member 2 factor activity, enhancer binding|morphogenesis|nucleus|nucleus| regulation of transcription, DNA- dependent|steroid hormone receptor activity|transcription|transcription factor activity|transcription from RNA polymerase II promoter miR-10b AA295257 NRP2 neuropilin 2 P + T angiogenesis|axon guidance|cell adhesion|cell adhesion|cell differentiation|electron transport|electron transporter activity|integral to membrane|integral to membrane|membrane|membrane fraction|neurogenesis|receptor activity|semaphorin receptor activity|vascular endothelial growth factor receptor activity|vascular endothelial growth factor receptor activity miR-10b NM_000430 PAFAH1B1 platelet-activating factor P + T astral microtubule|cell cortex|cell acetylhydrolase, isoform Ib, cycle|cell differentiation|cell alpha subunit 45 kDa motility|cytokinesis|cytoskeleton|dynein binding|establishment of mitotic spindle orientation|kinetochore|lipid metabolism|microtubule associated complex|microtubule-based process|mitosis|neurogenesis|nuclear membrane|signal transduction miR-10b NM_013382 POMT2 putative protein O- P + T O-linked glycosylation|dolichyl- mannosyltransferase phosphate-mannose-protein mannosyltransferase activity|endoplasmic reticulum|integral to membrane|magnesium ion binding|membrane|transferase activity, transferring glycosyl groups miR-10b BF337790 PURB purine-rich element binding P + T protein B miR-10b AI302106 RAP2A RAP2A, member of RAS P + T GTP binding|GTPase oncogene family activity|membrane|signal transduction|small GTPase mediated signal transduction miR-10b NM_002886 RAP2B RAP2B, member of RAS P + T GTP binding|protein transport|small oncogene family GTPase mediated signal transduction miR-10b NM_014781 RB1CC1 RB1-inducible coiled-coil 1 P + T kinase activity miR-10b NM_012234 RYBP RING1 and YY1 binding P + T development|negative regulation of protein transcription from RNA polymerase II promoter|nucleus|transcription corepressor activity miR-10b NM_005506 SCARB2 scavenger receptor class B, P + T cell adhesion|integral to plasma member 2 membrane|lysosomal membrane|membrane fraction|receptor activity miR-10b AF225986 SCN3A sodium channel, voltage- P + T cation channel activity|cation gated, type III, alpha transport|integral to polypeptide membrane|membrane|sodium ion transport|voltage-gated sodium channel activity|voltage-gated sodium channel complex miR-10b NM_002997 SDC1 syndecan 1 P + T cytoskeletal protein binding|integral to plasma membrane|membrane miR-10b NM_006924 SFRS1 splicing factor, P + T RNA binding|mRNA splice site arginine/serine-rich 1 selection|nuclear mRNA splicing, via (splicing factor 2, alternate spliceosome|nucleotide splicing factor) binding|nucleus miR-10b AI809967 SHC1 SHC (Src homology 2 P + T activation of MAPK|activation of domain containing) MAPK|intracellular signaling transforming protein 1 cascade|phospholipid binding|phospholipid binding|plasma membrane|plasma membrane|positive regulation of cell proliferation|positive regulation of cell proliferation|positive regulation of mitosis|positive regulation of mitosis|regulation of cell growth|regulation of epidermal growth factor receptor activity|transmembrane receptor protein tyrosine kinase adaptor protein activity|transmembrane receptor protein tyrosine kinase adaptor protein activity miR-10b NM_018976 SLC38A2 solute carrier family 38, P + T amino acid transport|amino acid- member 2 polyamine transporter activity|integral to membrane|membrane|oxygen transport|oxygen transporter activity|transport miR-10b NM_003794 SNX4 sorting nexin 4 P + T endocytosis|intracellular signaling cascade|protein transport miR-10b NM_003103 SON SON DNA binding protein P + T DNA binding|DNA binding|anti- apoptosis|double-stranded RNA binding|intracellular|nucleic acid binding|nucleus miR-10b Z48199 syndecan-1 P + T miR-10b NM_003222 TFAP2C transcription factor AP-2 P + T cell-cell signaling|nucleus|regulation gamma (activating enhancer of transcription from RNA binding protein 2 gamma) polymerase II promoter|transcription|transcription factor activity miR-10b NM_003275 TMOD1 tropomodulin P + T actin binding|cytoskeleton|cytoskeleton organization and biogenesis|tropomyosin binding miR-10b NM_003367 USF2 upstream transcription factor P + T RNA polymerase II transcription 2, c-fos interacting factor activity|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity miR-10b N62196 ZNF367 zinc finger protein 367 P + T nucleic acid binding|nucleus|zinc ion binding miR-125b AI948503 ABCC4 ATP-binding cassette, sub- P + T 15-hydroxyprostaglandin family C (CFTR/MRP), dehydrogenase (NAD+) activity|ATP member 4 binding|ATPase activity|ATPase activity, coupled to transmembrane movement of substances|chloride channel activity|integral to membrane|ion transport|membrane miR-125b AL534702 ABHD3 abhydrolase domain M + P + T containing 3 miR-125b AL527773 ABR active BCR-related gene P + T GTPase activator activity|guanyl- nucleotide exchange factor activity|small GTPase mediated signal transduction miR-125b NM_020039 ACCN2 amiloride-sensitive cation P + T amiloride-sensitive sodium channel channel 2, neuronal activity|integral to plasma membrane|ion channel activity|ion transport|membrane|response to pH|signal transduction|sodium ion transport miR-125b NM_003816 ADAM9 a disintegrin and P + T SH3 domain binding|integral to metalloproteinase domain 9 plasma membrane|integrin (meltrin gamma) binding|metalloendopeptidase activity|protein binding|protein kinase binding|protein kinase cascade|proteolysis and peptidolysis|zinc ion binding miR-125b L05500 ADCY1 adenylate cyclase 1 (brain) P + T cAMP biosynthesis|calcium- and calmodulin-responsive adenylate cyclase activity|calmodulin binding|integral to membrane|intracellular signaling cascade|magnesium ion binding miR-125b NM_017488 ADD2 adducin 2 (beta) P + T actin binding|actin cytoskeleton|calmodulin binding|membrane miR-125b NM_003488 AKAP1 A kinase (PRKA) anchor P + T RNA binding|integral to protein 1 membrane|mitochondrion|outer membrane miR-125b NM_005465 AKT3 v-akt murine thymoma viral P + T ATP binding|protein amino acid oncogene homolog 3 phosphorylation|protein (protein kinase B, gamma) serine/threonine kinase activity|signal transduction|transferase activity miR-125b NM_001150 ANPEP alanyl (membrane) P + T aminopeptidase aminopeptidase activity|angiogenesis|cell (aminopeptidase N, differentiation|integral to plasma aminopeptidase M, membrane|membrane alanyl microsomal aminopeptidase, aminopeptidase CD13, p150) activity|metallopeptidase activity|proteolysis and peptidolysis|receptor activity|zinc ion binding miR-125b AF193759 APBA2BP amyloid beta (A4) precursor M + P + T Golgi cis cisterna|Golgi cis protein-binding, family A, cisterna|antibiotic member 2 binding protein biosynthesis|calcium ion binding|cytoplasm|cytoplasm|endoplasmic reticulum membrane|endoplasmic reticulum membrane|nucleus|oxidoreductase activity|protein binding|protein binding|protein binding|protein metabolism|protein metabolism|protein secretion|protein secretion|regulation of amyloid precursor protein biosynthesis miR-125b NM_000038 APC adenomatosis polyposis coli P + T Wnt receptor signaling pathway|beta- catenin binding|cell adhesion|microtubule binding|negative regulation of cell cycle|protein complex assembly|signal transduction miR-125b NM_001655 ARCN1 archain 1 P + T COPI vesicle coat|Golgi apparatus|clathrin vesicle coat|intra- Golgi transport|intracellular protein transport|intracellular protein transport|membrane|retrograde transport, Golgi to ER|transport miR-125b BC001719 ASB6 ankyrin repeat and SOCS M + P intracellular signaling cascade box-containing 6 miR-125b AI478147 ATP10D ATPase, Class V, type 10D P + T ATP binding|ATPase activity|cation transport|hydrolase activity|integral to membrane|magnesium ion binding|membrane|phospholipid- translocating ATPase activity miR-125b NM_012069 ATP1B4 ATPase, (Na+)/K+ P + T hydrogen ion transporter transporting, beta 4 activity|integral to plasma polypeptide membrane|ion transport|membrane|potassium ion transport|proton transport|sodium ion transport|sodium:potassium- exchanging ATPase activity miR-125b NM_005176 ATP5G2 ATP synthase, H+ M + P + T ATP synthesis coupled proton transporting, mitochondrial transport|hydrogen-transporting ATP F0 complex, subunit c synthase activity, rotational (subunit 9), isoform 2 mechanism|hydrogen-transporting ATPase activity, rotational mechanism|ion transport|lipid binding|membrane|membrane fraction|mitochondrion|proton transport|proton-transporting ATP synthase complex (sensu Eukaryota)|proton-transporting two- sector ATPase complex|transporter activity miR-125b NM_001702 BAI1 brain-specific angiogenesis M + P + T G-protein coupled receptor inhibitor 1 activity|axonogenesis|brain-specific angiogenesis inhibitor activity|cell adhesion|integral to plasma membrane|intercellular junction|negative regulation of cell proliferation|neuropeptide signaling pathway|peripheral nervous system development|plasma membrane|protein binding|receptor activity|signal transduction miR-125b NM_001188 BAK1 BCL2-antagonist/killer 1 M + T apoptotic mitochondrial changes|induction of apoptosis|integral to membrane|protein heterodimerization activity|regulation of apoptosis miR-125b NM_013449 BAZ2A bromodomain adjacent to P + T DNA binding|chromatin zinc finger domain, 2A remodeling|nucleolus organizer complex|nucleus|regulation of transcription, DNA- dependent|transcription|transcription regulator activity miR-125b NM_004634 BRPF1 bromodomain and PHD M + P + T DNA finger containing, 1 binding|nucleus|nucleus|regulation of transcription, DNA- dependent|transcription|zinc ion binding miR-125b NM_003458 BSN bassoon (presynaptic P + T cytoskeleton|metal ion cytomatrix protein) binding|nucleus|structural constituent of cytoskeleton|synapse|synaptic transmission|synaptosome miR-125b NM_018108 C14orf130 hypothetical protein P + T ubiquitin cycle|ubiquitin-protein FLJ10483 ligase activity miR-125b AA025877 C20orf136 chromosome 20 open P + T reading frame 136 miR-125b AB054985 CACNB1 calcium channel, voltage- M + P + T calcium ion transport|ion dependent, beta 1 subunit transport|membrane fraction|muscle contraction|voltage-gated calcium channel activity|voltage-gated calcium channel complex miR-125b NM_001224 CASP2 caspase 2, apoptosis-related P + T anti-apoptosis|apoptotic cysteine protease (neural program|caspase activity|caspase precursor cell expressed, activity|caspase activity|cysteine- developmentally down- type peptidase activity|enzyme regulated 2) binding|intracellular|protein binding|proteolysis and peptidolysis|proteolysis and peptidolysis|regulation of apoptosis miR-125b NM_001755 CBFB core-binding factor, beta M + P + T RNA polymerase II transcription subunit factor activity|nucleus|transcription coactivator activity|transcription factor activity|transcription from RNA polymerase II promoter miR-125b AV648364 CBX7 ESTs, Highly similar to P + T chromatin|chromatin assembly or potassium voltage-gated disassembly|chromatin channel, Isk-related binding|chromatin subfamily, gene 4; modification|nucleus|regulation of potassium voltage-gated transcription, DNA- channel-like protein, Isk- dependent|transcription related subfamily [Homo sapiens] [H. sapiens] miR-125b NM_001408 CELSR2 cadherin, EGF LAG seven- M + P + T G-protein coupled receptor pass G-type receptor 2 activity|calcium ion binding|cell (flamingo homolog, adhesion|development|homophilic Drosophila) cell adhesion|integral to membrane|membrane|neuropeptide signaling pathway|receptor activity|signal transduction|structural molecule activity miR-125b NM_015955 CGI-27 C21orf19-like protein P + T miR-125b AF263462 CGN cingulin P + T actin binding|biological_process unknown|motor activity|myosin|protein binding|tight junction miR-125b AF064491 CLIM2 LIM domain binding 1 P + T LIM domain binding|development|development|negative regulation of transcription, DNA- dependent|nucleus|transcription cofactor activity|transcriptional repressor activity miR-125b AU152178 CMG2 capillary morphogenesis P + T integral to membrane|receptor protein 2 activity miR-125b NM_004073 CNK cytokine-inducible kinase P + T ATP binding|protein amino acid phosphorylation|protein binding|protein serine/threonine kinase activity|regulation of cell cycle|transferase activity miR-125b NM_020348 CNNM1 cyclin M1 M + P + T fatty acid biosynthesis miR-125b NM_022730 COPS7B COP9 constitutive M + P + T signalosome complex photomorphogenic homolog subunit 7B (Arabidopsis) miR-125b NM_003389 CORO2A coronin, actin binding P + T actin binding|glutamate-ammonia protein, 2A ligase activity|glutamine biosynthesis|intracellular signaling cascade|nitrogen compound metabolism|protein binding miR-125b BF939649 CORO2B coronin, actin binding P + T actin binding|actin cytoskeleton|actin protein, 2B cytoskeleton organization and biogenesis|membrane miR-125b NM_007007 CPSF6 cleavage and P + T RNA binding|mRNA polyadenylation specific processing|nucleic acid factor 6, 68 kDa binding|nucleotide binding|nucleus miR-125b NM_004386 CSPG3 chondroitin sulfate P + T calcium ion binding|cell proteoglycan 3 (neurocan) adhesion|cell motility|hyaluronic acid binding|sugar binding miR-125b NM_004393 DAG1 dystroglycan 1 (dystrophin- M + P + T actin cytoskeleton|calcium ion associated glycoprotein 1) binding|extracellular matrix (sensu Metazoa)|integral to plasma membrane|laminin receptor activity|membrane fraction|muscle contraction|plasma membrane|protein binding|protein complex assembly miR-125b NM_014764 DAZAP2 DAZ associated protein 2 P + T miR-125b NM_030927 DC-TM4F2 tetraspanin similar to P + T integral to membrane TM4SF9 miR-125b NM_004082 DCTN1 dynactin 1 (p150, glued M + P + T cytoplasm|cytoskeleton|dynein homolog, Drosophila) complex|mitosis|motor activity|neurogenesis miR-125b NM_030621 DICER1 Dicer1, Dcr-1 homolog P + T ATP binding|ATP-dependent (Drosophila) helicase activity|RNA interference, targeting of mRNA for destruction|RNA processing|double- stranded RNA binding|endonuclease activity|hydrolase activity|intracellular|ribonuclease III activity miR-125b U53506 DIO2 deiodinase, iodothyronine, P + T integral to type II membrane|membrane|selenium binding|selenocysteine incorporation|thyroid hormone generation|thyroxine 5′-deiodinase activity|thyroxine 5′-deiodinase activity miR-125b AL136139 dJ761I2.1 P + T miR-125b AL357503 dJ899C14.1 Q9H4T4 like P + T miR-125b AL117482 DKFZP434C131 DKFZP434C131 protein P + T ATP binding|protein amino acid phosphorylation|protein serine/threonine kinase activity|protein-tyrosine kinase activity|transferase activity miR-125b AK023580 DKFZP434H0820 hypothetical protein P + T DKFZp434H0820 miR-125b T16388 DKFZp564A176 hypothetical protein P + T development|integral to DKFZp564A176 membrane|membrane|receptor activity|semaphorin receptor activity miR-125b AL137517 DKFZp564O1278 hypothetical protein P + T integral to membrane DKFZp564O1278 miR-125b BE781961 DKFZp762A2013 hypothetical protein P + T electron transport|electron DKFZp762A2013 transporter activity miR-125b AB036931 DLL4 delta-like 4 (Drosophila) M + P + T Notch binding|Notch signaling pathway|cell differentiation|circulation|integral to membrane|membrane|signal transduction miR-125b NM_012266 DNAJB5 DnaJ (Hsp40) homolog, P + T heat shock protein binding|protein subfamily B, member 5 folding|response to unfolded protein|unfolded protein binding miR-125b NM_005740 DNAL4 dynein, axonemal, light P + T ATPase activity, coupled|axonemal polypeptide 4 dynein complex|microtubule motor activity|microtubule-based movement miR-125b BF593175 DOCK3 dedicator of cyto-kinesis 3 P + T GTP binding|GTPase binding|guanyl-nucleotide exchange factor activity miR-125b NM_006426 DPYSL4 dihydropyrimidinase-like 4 P + T hydrolase activity|neurogenesis miR-125b NM_006465 DRIL2 dead ringer (Drosophila)- P + T DNA binding|biological_process like 2 (bright and dead unknown|nucleus ringer) miR-125b BC005047 DUSP6 dual specificity phosphatase 6 P + T MAP kinase phosphatase activity|cytoplasm|hydrolase activity|inactivation of MAPK|protein amino acid dephosphorylation|protein serine/threonine phosphatase activity|protein tyrosine phosphatase activity|regulation of cell cycle|soluble fraction miR-125b NM_004423 DVL3 dishevelled, dsh homolog 3 P + T development|frizzled signaling (Drosophila) pathway|heart development|intracellular|intracellular signaling cascade|kinase activity|neurogenesis|protein binding|signal transducer activity miR-125b NM_001949 E2F3 E2F transcription factor 3 P + T nucleus|protein binding|regulation of cell cycle|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcription factor complex|transcription initiation from RNA polymerase II promoter miR-125b AU149385 EAF1 Homo sapiens cDNA P + T FLJ13155 fis, clone NT2RP3003433, mRNA sequence miR-125b NM_014674 EDEM KIAA0212 gene product P + T ER-associated protein catabolism|GTP binding|N-linked glycosylation|calcium ion binding|endoplasmic reticulum|integral to endoplasmic reticulum membrane|integral to membrane|mannosyl-oligosaccharide 1,2-alpha-mannosidase activity|membrane|protein binding|response to unfolded protein miR-125b NM_001955 EDN1 endothelin 1 M + P + T cell-cell signaling|extracellular space|hormone activity|pathogenesis|positive regulation of cell proliferation|regulation of blood pressure|regulation of vasoconstriction|signal transduction|soluble fraction miR-125b AI832074 EIF2C2 eukaryotic translation M + P cellular_component unknown|protein initiation factor 2C, 2 biosynthesis|translation initiation factor activity miR-125b AB044548 EIF4EBP1 eukaryotic translation P + T eukaryotic initiation factor 4E initiation factor 4E binding binding|negative regulation of protein 1 protein biosynthesis|negative regulation of translational initiation|regulation of translation miR-125b NM_020390 EIF5A2 eukaryotic translation P + T DNA binding|protein initiation factor 5A2 biosynthesis|translation initiation factor activity|translational initiation miR-125b NM_004438 EPHA4 EphA4 P + T ATP binding|ephrin receptor activity|integral to plasma membrane|membrane|protein amino acid phosphorylation|receptor activity|signal transduction|transferase activity|transmembrane receptor protein tyrosine kinase signaling pathway miR-125b NM_004451 ESRRA estrogen-related receptor P + T nucleus|regulation of transcription, alpha DNA-dependent|steroid binding|steroid hormone receptor activity|transcription|transcription factor activity miR-125b NM_004907 ETR101 immediate early protein P + T miR-125b NM_005238 ETS1 v-ets erythroblastosis virus P + T RNA polymerase II transcription E26 oncogene homolog 1 factor activity|immune (avian) response|negative regulation of cell proliferation|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcription from RNA polymerase II promoter miR-125b NM_001987 ETV6 ets variant gene 6 (TEL P + T nucleus|regulation of transcription, oncogene) DNA- dependent|transcription|transcription factor activity miR-125b NM_022763 FAD104 FAD104 P + T miR-125b AF308300 FAPP2 phosphoinositol 4-phosphate P + T adaptor protein-2 miR-125b NM_022976 FGFR2 fibroblast growth factor M + P + T ATP binding|cell growth|fibroblast receptor 2 (bacteria- growth factor receptor expressed kinase, activity|heparin binding|integral to keratinocyte growth factor membrane|membrane|protein amino receptor, craniofacial acid phosphorylation|protein amino dysostosis 1, Crouzon acid phosphorylation|protein syndrome, Pfeiffer serine/threonine kinase syndrome, Jackson-Weiss activity|protein-tyrosine kinase syndrome) activity|protein-tyrosine kinase activity|receptor activity|transferase activity miR-125b NM_004470 FKBP2 FK506 binding protein 2, P + T FK506 binding|endoplasmic 13 kDa reticulum|isomerase activity|peptidyl-prolyl cis-trans isomerase activity|protein folding miR-125b AL160175 FKHL18 forkhead-like 18 P + T (Drosophila) miR-125b BF515132 FLJ00024 hypothetical protein P + T FLJ00024 miR-125b BC002945 FLJ10101 hypothetical protein M + P GTP binding|protein transport|small FLJ10101 GTPase mediated signal transduction miR-125b NM_018243 FLJ10849 hypothetical protein P + T GTP binding|cell cycle|cytokinesis FLJ10849 miR-125b NM_019084 FLJ10895 hypothetical protein P + T nucleus|regulation of cell cycle FLJ10895 miR-125b NM_018320 FLJ11099 hypothetical protein P + T protein ubiquitination|ubiquitin FLJ11099 ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-125b NM_018375 FLJ11274 hypothetical protein M + P + T membrane|metal ion transport|metal FLJ11274 ion transporter activity miR-125b NM_024954 FLJ11807 hypothetical protein P + T protein modification FLJ11807 miR-125b BF434995 FLJ14708 hypothetical protein P + T FLJ14708 miR-125b NM_018992 FLJ20040 hypothetical protein P + T membrane|potassium ion FLJ20040 transport|protein binding|voltage- gated potassium channel activity|voltage-gated potassium channel complex miR-125b NM_017911 FLJ20635 hypothetical protein P + T FLJ20635 miR-125b NM_017936 FLJ20707 hypothetical protein M + P + T ATP synthesis coupled proton FLJ20707 transport|cytoplasm|hydrogen- transporting ATP synthase activity, rotational mechanism|hydrogen- transporting ATPase activity, rotational mechanism|membrane|phosphate transport|proton-transporting two- sector ATPase complex miR-125b NM_024789 FLJ22529 hypothetical protein P + T FLJ22529 miR-125b AA721230 FLJ25604 hypothetical protein P + T guanyl-nucleotide exchange factor FLJ25604 activity|small GTPase mediated signal transduction miR-125b AI677701 FLJ30829 hypothetical protein P + T nucleic acid binding|nucleotide FLJ30829 binding miR-125b NM_004475 FLOT2 flotillin 2 M + P + T cell adhesion|epidermis development|flotillin complex|integral to membrane|plasma membrane|protein binding miR-125b AA830884 FMR1 fragile X mental retardation 1 M + T mRNA binding|mRNA processing|mRNA-nucleus export|nucleoplasm|polysome|ribo- some|soluble fraction|transport miR-125b AF305083 FUT4 fucosyltransferase 4 (alpha P + T Golgi apparatus|L-fucose (1,3) fucosyltransferase, catabolism|alpha(1,3)- myeloid-specific) fucosyltransferase activity|carbohydrate metabolism|integral to membrane|membrane|membrane fraction|protein amino acid glycosylation|transferase activity, transferring glycosyl groups miR-125b X92762 G4.5 tafazzin (cardiomyopathy, M + P + T acyltransferase activity|heart dilated 3A (X-linked); development|integral to endocardial fibroelastosis 2; membrane|metabolism|muscle Barth syndrome) contraction|muscle development miR-125b NM_012296 GAB2 GRB2-associated binding P + T protein 2 miR-125b NM_015044 GGA2 golgi associated, gamma M + T ADP-ribosylation factor adaptin ear containing, ARF binding|Golgi stack|Golgi trans face| binding protein 2 clathrin coat of trans-Golgi network vesicle|intra-Golgi transport|intracellular protein transport|intracellular protein transport|membrane|protein complex assembly|protein transporter activity miR-125b AL049709 GGTL3 gamma-glutamyltransferase- M + P + T like 3 miR-125b NM_000165 GJA1 gap junction protein, alpha P + T cell-cell signaling|connexon channel 1, 43 kDa (connexin 43) activity|connexon complex|gap junction assembly|heart development|integral to plasma membrane|ion transporter activity|muscle contraction|perception of sound|positive regulation of I- kappaB kinase/NF-kappaB cascade|protein binding|signal transducer activity|transport miR-125b NM_014905 GLS glutaminase P + T glutaminase activity|glutamine catabolism|hydrolase activity|mitochondrion miR-125b NM_005113 GOLGA5 golgi autoantigen, golgin P + T ATP binding|Golgi membrane|cell subfamily a, 5 surface receptor linked signal transduction|integral to plasma membrane|protein amino acid phosphorylation|protein-tyrosine kinase activity miR-125b NM_001448 GPC4 glypican 4 M + P + T cell proliferation|extracellular matrix (sensu Metazoa)|integral to plasma membrane|membrane|morphogenesis miR-125b NM_005296 GPR23 G protein-coupled receptor M + T G-protein coupled receptor protein 23 signaling pathway|integral to plasma membrane|purinergic nucleotide receptor activity, G-protein coupled|receptor activity|rhodopsin- like receptor activity|signal transduction miR-125b U66065 GRB10 growth factor receptor- M + T SH3/SH2 adaptor activity|cell-cell bound protein 10 signaling|cytoplasm|insulin receptor signaling pathway|intracellular signaling cascade|plasma membrane miR-125b NM_021643 GS3955 GS3955 protein P + T ATP binding|protein amino acid phosphorylation|protein kinase activity|transferase activity miR-125b NM_019096 GTPBP2 GTP binding protein 2 M + T GTP binding|GTPase activity|protein biosynthesis|small GTPase mediated signal transduction miR-125b U78181 hBNaC2 amiloride-sensitive cation P + T amiloride-sensitive sodium channel channel 2, neuronal activity|integral to plasma membrane|ion channel activity|ion transport|membrane|response to pH|signal transduction|sodium ion transport miR-125b NM_005477 HCN4 hyperpolarization activated P + T 3′,5′-cAMP binding|cation channel cyclic nucleotide-gated activity|cation potassium channel 4 transport|circulation|integral to plasma membrane|membrane|membrane fraction|muscle contraction|nucleotide binding|potassium ion transport|sodium ion transport|voltage-gated potassium channel activity miR-125b NM_002112 HDC histidine decarboxylase P + T amino acid metabolism|catecholamine biosynthesis|histidine decarboxylase activity|histidine metabolism|lyase activity miR-125b U64317 HEF1 enhancer of filamentation 1 P + T actin filament bundle formation|cell (cas-like docking; Crk- adhesion|cytokinesis|cytoplasm|cyto- associated substrate related) skeleton|cytoskeleton organization and biogenesis|integrin-mediated signaling pathway|mitosis|nucleus|protein binding|regulation of cell cycle|regulation of cell growth|signal transduction|spindle miR-125b L38487 hERRa estrogen-related receptor P + T nucleus|regulation of transcription, alpha DNA-dependent|steroid binding|steroid hormone receptor activity|transcription|transcription factor activity miR-125b AB028943 HIC2 hypermethylated in cancer 2 P + T DNA binding|negative regulation of transcription, DNA- dependent|nucleus|protein C- terminus binding|transcription|zinc ion binding miR-125b AL023584 HIVEP2 human immunodeficiency P + T virus type I enhancer binding protein 2 miR-125b AL023584 HIVEP2 human immunodeficiency P + T virus type I enhancer binding protein 2 miR-125b NM_005342 HMGB3 high-mobility group box 3 P + T DNA bending activity|DNA binding|chromatin|development|nu- cleus|regulation of transcription, DNA- dependent miR-125b AL031295 HMGCL; HL lysophospholipase II M + P + T miR-125b NM_004503 HOXC6 homeo box C6 P + T development|development|nucleus|regulation of transcription from RNA polymerase II promoter|regulation of transcription, DNA- dependent|transcription corepressor activity|transcription factor activity miR-125b AA844682 HRD1 HRD1 protein P + T protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-125b AL136667 HSPC039 HSPC039 protein P + T integral to membrane miR-125b AF245044 HT023 hypothetical protein HT023 P + T miR-125b U13022 Ich-1 caspase 2, apoptosis-related P + T anti-apoptosis|apoptotic cysteine protease (neural program|caspase activity|caspase precursor cell expressed, activity|caspase activity|cysteine- developmentally down- type peptidase activity|enzyme regulated 2) binding|intracellular|protein binding|proteolysis and peptidolysis|proteolysis and peptidolysis|regulation of apoptosis miR-125b NM_004513 IL16 interleukin 16 (lymphocyte M + P + T chemotaxis|cytokine chemoattractant factor) activity|extracellular space|immune response|protein binding|sensory perception miR-125b NM_002460 IRF4 interferon regulatory factor 4 P + T RNA polymerase II transcription factor activity|T-cell activation|T-cell activation|nucleus|nucleus|nucleus|positive regulation of interleukin-10 biosynthesis|positive regulation of interleukin-10 biosynthesis|positive regulation of interleukin-13 biosynthesis|positive regulation of interleukin-13 biosynthesis|positive regulation of interleukin-2 biosynthesis|positive regulation of interleukin-2 biosynthesis|positive regulation of interleukin-4 biosynthesis|positive regulation of interleukin-4 biosynthesis|positive regulation of transcription|positive regulation of transcription|regulation of T-helper cell differentiation|regulation of T-helper cell differentiation|regulation of transcription, DNA- dependent|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcription factor activity|transcription factor binding|transcription factor binding|transcriptional activator activity|transcriptional activator activity miR-125b NM_002207 ITGA9 integrin, alpha 9 P + T cell-matrix adhesion|integral to membrane|integrin complex|integrin- mediated signaling pathway|protein binding|receptor activity miR-125b NM_000212 ITGB3 integrin, beta 3 (platelet P + T blood coagulation|cell-matrix glycoprotein IIIa, antigen adhesion|integrin complex|integrin- CD61) mediated signaling pathway|protein binding|receptor activity miR-125b NM_021991 JUP junction plakoglobin P + T cell adhesion|cell adhesion|cytoplasm|cytoskeletal protein binding|cytoskeleton|cytoskeleton|membrane fraction|mitotic chromosome condensation|protein binding|soluble fraction|structural molecule activity miR-125b AF032897 KCNH7 potassium voltage-gated P + T cation transport|integral to channel, subfamily H (eag- membrane|membrane|potassium ion related), member 7 transport|regulation of transcription, DNA-dependent|signal transducer activity|signal transduction|voltage- gated potassium channel activity miR-125b NM_002252 KCNS3 potassium voltage-gated M + P + T cation transport|delayed rectifier channel, delayed-rectifier, potassium channel subfamily S, member 3 activity|membrane|membrane fraction|potassium channel regulator activity|potassium ion transport|protein binding|voltage- gated potassium channel complex miR-125b NM_014735 KIAA0215 KIAA0215 gene product P + T DNA binding|regulation of transcription, DNA-dependent miR-125b NM_015288 KIAA0239 KIAA0239 protein P + T DNA binding|regulation of transcription, DNA-dependent miR-125b D87469 KIAA0279 cadherin, EGF LAG seven- M + P + T G-protein coupled receptor pass G-type receptor 2 activity|calcium ion binding|cell (flamingo homolog, adhesion|development|homophilic Drosophila) cell adhesion|integral to membrane|membrane|neuropeptide signaling pathway|receptor activity|signal transduction|structural molecule activity miR-125b AB002356 KIAA0358 MAP-kinase activating P + T cell surface receptor linked signal death domain transduction|cytoplasm|death receptor binding|kinase activity|plasma membrane|protein kinase activator activity miR-125b NM_014871 KIAA0710 KIAA0710 gene product P + T cysteine-type endopeptidase activity|exonuclease activity|nucleus|ubiquitin cycle|ubiquitin thiolesterase activity|ubiquitin-dependent protein catabolism miR-125b AB018333 KIAA0790 KIAA0790 protein P + T cell cycle|negative regulation of cell cycle miR-125b NM_014912 KIAA0940 KIAA0940 protein P + T nucleic acid binding miR-125b AB028957 KIAA1034 KIAA1034 protein P + T DNA binding|nucleus|regulation of transcription, DNA- dependent|transcription factor activity miR-125b NM_014901 KIAA1100 KIAA1100 protein M + P + T protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-125b AB033016 KIAA1190 hypothetical protein P + T DNA binding|nucleic acid KIAA1190 binding|nucleus|protein binding|regulation of transcription, DNA-dependent|zinc ion binding miR-125b AA056548 KIAA1268 KIAA1268 protein P + T NAD+ ADP-ribosyltransferase activity|nucleus|protein amino acid ADP-ribosylation miR-125b BE670098 KIAA1594 KIAA1594 protein M + P + T cysteine-type endopeptidase activity|ubiquitin cycle|ubiquitin thiolesterase activity|ubiquitin- dependent protein catabolism miR-125b AU157109 KIAA1598 KIAA1598 protein P + T miR-125b AA772278 KIAA1673 KIAA1673 P + T miR-125b NM_015995 KLF13 Kruppel-like factor 13 P + T DNA binding|RNA polymerase II transcription factor activity|nucleus|regulation of transcription, DNA- dependent|transcription|transcription from RNA polymerase II promoter|zinc ion binding miR-125b NM_016531 KLF3 Kruppel-like factor 3 (basic) P + T development|negative regulation of transcription from RNA polymerase II promoter|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity|zinc ion binding miR-125b BE892574 LACTB lactamase, beta P + T hydrolase activity|integral to membrane|response to antibiotic miR-125b BE566136 LBP-32 LBP protein 32 P + T miR-125b NM_024090 LCE long-chain fatty-acyl P + T integral to membrane elongase miR-125b NM_003893 LDB1 LIM domain binding 1 P + T LIM domain binding|development|development|negative regulation of transcription, DNA- dependent|nucleus|transcription cofactor activity|transcriptional repressor activity miR-125b U94354 LFNG lunatic fringe homolog M + T Golgi (Drosophila) apparatus|development|extracellular region|integral to membrane|membrane|organo- genesis|transferase activity, transferring glycosyl groups miR-125b NM_002310 LIFR leukemia inhibitory factor M + P + T cell surface receptor linked signal receptor transduction|integral to plasma membrane|leukemia inhibitory factor receptor activity|membrane|receptor activity miR-125b NM_016339 Link-GEFII Link guanine nucleotide P + T G-protein coupled receptor protein exchange factor II signaling pathway|guanyl-nucleotide exchange factor activity|membrane fraction|neurogenesis|small GTPase mediated signal transduction miR-125b NM_005575 LNPEP leucyl/cystinyl P + T aminopeptidase activity|cell-cell aminopeptidase signaling|integral to plasma membrane|membrane alanyl aminopeptidase activity|metallopeptidase activity|plasma membrane|pregnancy|proteolysis and peptidolysis|zinc ion binding miR-125b AL031186 LOC129080 putative emu1 P + T miR-125b AI884701 LOC221002 CG4853 gene product M + P guanyl-nucleotide exchange factor activity|small GTPase mediated signal transduction miR-125b AI953847 LOC255488 Homo sapiens mRNA full P + T electron transport|electron length insert cDNA clone transporter activity|integral to EUROIMAGE 186647, membrane|iron ion binding|ligase mRNA sequence activity|protein binding|protein ubiquitination during ubiquitin- dependent protein catabolism|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-125b NM_015899 LOC51054 putative glycolipid transfer P + T protein miR-125b AA209239 LOC57406 lipase protein P + T aromatic compound metabolism|hydrolase activity|response to toxin|xenobiotic metabolism miR-125b NM_005576 LOXL1 lysyl oxidase-like 1 M + P + T copper ion binding|electron transporter activity|extracellular region|oxidoreductase activity|protein modification|protein- lysine 6-oxidase activity miR-125b AA584297 LRP4 low density lipoprotein M + T calcium ion receptor-related protein 4 binding|endocytosis|integral to membrane|membrane|receptor activity miR-125b NM_007260 LYPLA2 lysophospholipase II M + P + T fatty acid metabolism|hydrolase activity|lipid metabolism miR-125b NM_004901 LYSAL1 lysosomal apyrase-like 1 P + T Golgi apparatus|UDP catabolism|apyrase activity|hydrolase activity|integral to Golgi membrane|integral to membrane|lysosome|magnesium ion binding|nucleobase, nucleoside, nucleotide and nucleic acid metabolism|uridine-diphosphatase activity|vacuolar membrane miR-125b NM_002355 M6PR mannose-6-phosphate M + P + T endosome to lysosome receptor (cation dependent) transport|integral to plasma membrane|lysosome|receptor mediated endocytosis|transmembrane receptor activity|transport|transporter activity miR-125b AB002356 MADD MAP-kinase activating P + T cell surface receptor linked signal death domain transduction|cytoplasm|death receptor binding|kinase activity|plasma membrane|protein kinase activator activity miR-125b NM_016219 MAN1B1 mannosidase, alpha, class P + T N-linked glycosylation|N-linked 1B, member 1 glycosylation|calcium ion binding|calcium ion binding|carbohydrate metabolism|endoplasmic reticulum|hydrolase activity, acting on glycosyl bonds|integral to membrane|mannosyl-oligosaccharide 1,2-alpha-mannosidase activity|mannosyl-oligosaccharide 1,2-alpha-mannosidase activity|membrane|membrane fraction|oligosaccharide metabolism miR-125b NM_002446 MAP3K10 mitogen-activated protein P + T ATP binding|JUN kinase kinase kinase kinase kinase 10 kinase activity|activation of JNK|autophosphorylation|induction of apoptosis|protein homodimerization activity|protein serine/threonine kinase activity|protein-tyrosine kinase activity|signal transduction|transferase activity miR-125b NM_002419 MAP3K11 mitogen-activated protein M + P + T ATP binding|G1 phase of mitotic cell kinase kinase kinase 11 cycle|JUN kinase kinase kinase activity|activation of JNK|autophosphorylation|cell proliferation|centrosome|microtubule| microtubule-based process|protein homodimerization activity|protein oligomerization|protein serine/threonine kinase activity|protein-tyrosine kinase activity|transferase activity miR-125b Z25432 MAPK14 mitogen-activated protein P + T ATP binding|MAP kinase kinase 14 activity|MAP kinase kinase activity|MP kinase activity|antimicrobial humoral response (sensu Vertebrata)|cell motility|cell surface receptor linked signal transduction|chemotaxis|cytoplasm|nu- cleus|protein amino acid phosphorylation|protein kinase cascade|protein serine/threonine kinase activity|protein-tyrosine kinase activity|response to stress|transferase activity miR-125b NM_018650 MARK1 MAP/microtubule affinity- P + T ATP regulating kinase 1 binding|cytoplasm|cytoskeleton|cytoskeleton organization and biogenesis|magnesium ion binding|microtubule cytoskeleton|protein amino acid phosphorylation|protein amino acid phosphorylation|protein kinase cascade|protein serine/threonine kinase activity|protein serine/threonine kinase activity|transferase activity miR-125b NM_001879 MASP1 mannan-binding lectin P + T calcium ion binding|chymotrypsin serine protease 1 (C4/C2 activity|complement activating component of Ra- activation|complement activation, reactive factor) classical pathway|extracellular region|immune response|peptidase activity|proteolysis and peptidolysis|trypsin activity miR-125b NM_005911 MAT2A methionine P + T ATP binding|magnesium ion adenosyltransferase II, alpha binding|methionine adenosyltransferase activity|one- carbon compound metabolism|transferase activity miR-125b NM_005920 MEF2D MADS box transcription P + T muscle enhancer factor 2, development|nucleus|regulation of polypeptide D (myocyte transcription, DNA- enhancer factor 2D) dependent|transcription|transcription coactivator activity|transcription factor activity|transcription from RNA polymerase II promoter miR-125b NM_020149 MEIS2 Meis1, myeloid ecotropic M + P negative regulation of transcription viral integration site 1 from RNA polymerase II homolog 2 (mouse) promoter|nucleus|regulation of transcription, DNA- dependent|specific RNA polymerase II transcription factor activity|transcription corepressor activity|transcription factor activity|transcription factor activity miR-125b NM_017927 MFN1 mitofusin 1 P + T GTP binding|GTPase activity|hydrolase activity|integral to membrane|mitochondrial fusion|mitochondrial outer membrane|mitochondrion miR-125b AI139252 MGC16063 ribosomal protein L35a P + T JAK-STAT cascade|acute-phase response|calcium ion binding|cell motility|cytoplasm|hematopoietin/interferon- class (D200-domain) cytokine receptor signal transducer activity|intracellular signaling cascade|negative regulation of transcription from RNA polymerase II promoter|neurogenesis|nucleus|nu- cleus|regulation of transcription, DNA- dependent|signal transducer activity|transcription|transcription factor activity|transcription factor activity miR-125b AI862120 MGC21981 hypothetical protein P + T membrane MGC21981 miR-125b AL515061 MGC24302 hypothetical protein P + T MGC24302 miR-125b BE618656 MGC2541 similar to RIKEN cDNA M + P + T 2610030J16 gene miR-125b BC005842 MGC2705 hypothetical protein P + T MGC2705 miR-125b NM_024293 MGC3035 hypothetical protein M + P MGC3035 miR-125b NM_017572 MKNK2 MAP kinase-interacting P + T ATP binding|ATP binding|cell serine/threonine kinase 2 surface receptor linked signal transduction|protein amino acid phosphorylation|protein amino acid phosphorylation|protein kinase cascade|protein serine/threonine kinase activity|protein serine/threonine kinase activity|protein-tyrosine kinase activity|regulation of translation|response to stress|transferase activity miR-125b NM_005439 MLF2 myeloid leukemia factor 2 P + T defense response|nucleus miR-125b NM_007359 MLN51 MLN51 protein P + T mRNA processing|mRNA-nucleus export|molecular_function unknown|nucleus|transport miR-125b NM_002442 MSI1 musashi homolog 1 M + P + T RNA (Drosophila) binding|neurogenesis|nucleotide binding|nucleus miR-125b NM_021090 MTMR3 myotubularin related protein 3 M + P + T cytoplasm|hydrolase activity|inositol or phosphatidylinositol phosphatase activity|membrane|membrane fraction|phospholipid dephosphorylation|protein amino acid dephosphorylation|protein serine/threonine phosphatase activity|protein tyrosine phosphatase activity|protein tyrosine/serine/threonine phosphatase activity|zinc ion binding miR-125b AK024501 MXD4 MAX dimerization protein 4 M + P + T DNA binding|negative regulation of cell proliferation|negative regulation of transcription from RNA polymerase II promoter|nucleus|protein binding|regulation of transcription, DNA- dependent|transcription|transcription corepressor activity miR-125b AB020642 MYT1 myelin transcription factor 1 M + P + T nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity|zinc ion binding miR-125b NM_004540 NCAM2 neural cell adhesion P + T cell adhesion|integral to molecule 2 membrane|membrane|neuron adhesion|plasma membrane|protein binding miR-125b NM_012338 NET-2 transmembrane 4 P + T integral to membrane|membrane superfamily member fraction tetraspan NET-2 miR-125b U84246 NEU1 sialidase 1 (lysosomal P + T carbohydrate metabolism|exo-alpha- sialidase) sialidase activity|hydrolase activity, acting on glycosyl bonds|lysosome miR-125b AI824012 NRIP1 nuclear receptor interacting P + T nucleus|regulation of transcription, protein 1 DNA- dependent|transcription|transcription coactivator activity miR-125b D81048 NRM nurim (nuclear envelope P + T membrane protein) miR-125b BC001794 NUMBL numb homolog P + T neurogenesis (Drosophila)-like miR-125b AB020713 NUP210 nucleoporin 210 P + T development|nucleus miR-125b NM_002537 OAZ2 ornithine decarboxylase M + P + T ornithine decarboxylase inhibitor antizyme 2 activity|polyamine metabolism miR-125b NM_024586 OSBPL9 oxysterol binding protein- P + T lipid transport|steroid metabolism like 9 miR-125b U64661 PABP ESTs, Highly similar to P + T PAB1_HUMAN Polyadenylate-binding protein 1 (Poly(A)-binding protein 1) (PABP 1) (PABP1) [H. sapiens] miR-125b AK000003 PCQAP PC2 (positive cofactor 2, P + T multiprotein complex) glutamine/Q-rich-associated protein miR-125b NM_004716 PCSK7 proprotein convertase M + P + T integral to Golgi membrane|integral subtilisin/kexin type 7 to membrane|peptidase activity|peptidase activity|peptide hormone processing|proteolysis and peptidolysis|subtilase activity miR-125b NM_006201 PCTK1 PCTAIRE protein kinase 1 M + P + T ATP binding|protein amino acid phosphorylation|protein amino acid phosphorylation|protein serine/threonine kinase activity|protein serine/threonine kinase activity|regulation of cell cycle|transferase activity miR-125b NM_021213 PCTP phosphatidylcholine transfer M + P + T cytosol|lipid binding|lipid protein transport|phosphatidylcholine transporter activity miR-125b NM_021255 PELI2 pellino homolog 2 M + P + T (Drosophila) miR-125b NM_002646 PIK3C2B phosphoinositide-3-kinase, P + T inositol or phosphatidylinositol class 2, beta polypeptide kinase activity|intracellular signaling cascade|microsome|phosphatidylinositol 3-kinase activity|phosphatidylinositol-4- phosphate 3-kinase activity|phosphoinositide 3-kinase complex|plasma membrane|transferase activity miR-125b NM_003628 PKP4 plakophilin 4 P + T cell adhesion|cytoskeleton|intercellular junction|protein binding|structural molecule activity miR-125b NM_006718 PLAGL1 pleiomorphic adenoma P + T DNA binding|cell cycle gene-like 1 arrest|induction of apoptosis|nucleic acid binding|nucleus|regulation of transcription, DNA- dependent|transcription|zinc ion binding miR-125b AI457120 PPAT phosphoribosyl P + T amidophosphoribosyltransferase pyrophosphate activity|glutamine amidotransferase metabolism|magnesium ion binding|metabolism|nucleoside metabolism|purine base biosynthesis|purine nucleotide biosynthesis|transferase activity, transferring glycosyl groups miR-125b NM_002719 PPP2R5C protein phosphatase 2, P + T hydrolase regulatory subunit B (B56), activity|nucleus|phosphoprotein gamma isoform phosphatase activity|protein phosphatase type 2A complex|protein phosphatase type 2A complex|protein phosphatase type 2A regulator activity|protein phosphatase type 2A regulator activity|signal transduction|signal transduction miR-125b AL022067 PRDM1 PR domain containing 1, P + T with ZNF domain miR-125b U23736 PRDM2 PR domain containing 2, P + T DNA binding|metal ion with ZNF domain binding|nucleus|nucleus|regulation of transcription|regulation of transcription, DNA- dependent|transcription factor activity|transcription regulator activity|zinc ion binding|zinc ion binding miR-125b AF083033 PRKRA protein kinase, interferon- P + T double-stranded RNA inducible double stranded binding|enzyme activator RNA dependent activator activity|immune response|intracellular|kinase activity|negative regulation of cell proliferation|response to virus|signal transducer activity|signal transduction miR-125b NM_014369 PTPN18 protein tyrosine P + T hydrolase activity|non-membrane phosphatase, non-receptor spanning protein tyrosine type 18 (brain-derived) phosphatase activity|protein amino acid dephosphorylation|protein amino acid dephosphorylation|protein tyrosine phosphatase activity miR-125b AI762627 PTPRF protein tyrosine P + T cell adhesion|hydrolase phosphatase, receptor type, F activity|integral to membrane|integral to plasma membrane|protein amino acid dephosphorylation|protein binding|protein tyrosine phosphatase activity|receptor activity|transmembrane receptor protein tyrosine phosphatase activity|transmembrane receptor protein tyrosine phosphatase signaling pathway miR-125b NM_002840 PTPRF protein tyrosine P + T cell adhesion|hydrolase phosphatase, receptor type, F activity|integral to membrane|integral to plasma membrane|protein amino acid dephosphorylation|protein binding|protein tyrosine phosphatase activity|receptor activity|transmembrane receptor protein tyrosine phosphatase activity|transmembrane receptor protein tyrosine phosphatase signaling pathway miR-125b AF142419 QKI homolog of mouse quaking P + T QKI (KH domain RNA binding protein) miR-125b NM_004283 RAB3D RAB3D, member RAS P + T GTP binding|GTPase oncogene family activity|exocytosis|hemocyte development|protein transport|small GTPase mediated signal transduction miR-125b BC002510 RAB6B RAB6B, member RAS P + T GTP binding|GTPase activity|Golgi oncogene family apparatus|intracellular protein transport|retrograde transport, Golgi to ER|small GTPase mediated signal transduction miR-125b AK022662 RASAL2 RAS protein activator like 2 P + T GTPase activator activity|Ras GTPase activator activity|signal transduction miR-125b NM_004841 RASAL2 RAS protein activator like 2 P + T GTPase activator activity|Ras GTPase activator activity|signal transduction miR-125b NM_016090 RBM7 RNA binding motif protein 7 P + T RNA binding|meiosis|nucleic acid binding|nucleotide binding miR-125b NM_006268 REQ requiem, apoptosis response M + P + T DNA binding|apoptosis|induction of zinc finger gene apoptosis by extracellular signals|nucleus|protein ubiquitination|regulation of transcription, DNA- dependent|transcription|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-125b NM_000449 RFX5 regulatory factor X, 5 P + T nucleus|regulation of transcription, (influences HLA class II DNA- expression) dependent|transcription|transcription coactivator activity|transcription factor activity|transcription from RNA polymerase II promoter miR-125b NM_003721 RFXANK regulatory factor X- P + T humoral immune associated ankyrin- response|nucleus|regulation of containing protein transcription, DNA- dependent|transcription|transcription coactivator activity|transcription factor activity|transcription from RNA polymerase II promoter miR-125b NM_014746 RNF144 likely ortholog of mouse P + T nucleus|protein ubiquitin conjugating ubiquitination|ubiquitin ligase enzyme 7 interacting protein 4 complex|ubiquitin-protein ligase activity|zinc ion binding miR-125b NM_014771 RNF40 ring finger protein 40 M + P + T protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-125b AL109955 RNPC1 RNA-binding region (RNP1, P + T RRM) containing 1 miR-125b AF116627 RPL29 ribosomal protein L29 M + T miR-125b NM_002953 RPS6KA1 ribosomal protein S6 kinase, M + P + T ATP binding|protein amino acid 90 kDa, polypeptide 1 phosphorylation|protein serine/threonine kinase activity|protein serine/threonine kinase activity|protein-tyrosine kinase activity|signal transduction|transferase activity miR-125b NM_000332 SCA1 spinocerebellar ataxia 1 P + T RNA binding|cytoplasm|nucleus (olivopontocerebellar ataxia 1, autosomal dominant, ataxin 1) miR-125b NM_012429 SEC14L2 SEC14-like 2 (S. cerevisiae) P + T cytoplasm|intracellular protein transport|membrane|nucleus|phospho- lipid binding|positive regulation of transcription, DNA- dependent|protein carrier activity|regulation of cholesterol biosynthesis|transcription|transcriptional activator activity|transport|vitamin E binding miR-125b NM_005065 SEL1L sel-1 suppressor of lin-12- P + T catalytic activity|integral to like (C. elegans) membrane miR-125b NM_017789 SEMA4C sema domain, M + P + T cell differentiation|integral to immunoglobulin domain membrane|membrane|neurogenesis|receptor (Ig), transmembrane domain activity (TM) and short cytoplasmic domain, (semaphorin) 4C miR-125b NM_006378 SEMA4D sema domain, P + T anti-apoptosis|cell adhesion|cell immunoglobulin domain differentiation|immune (Ig), transmembrane domain response|integral to (TM) and short cytoplasmic membrane|membrane|neurogenesis|receptor domain, (semaphorin) 4D activity miR-125b BE622841 SENP2 sentrin-specific protease M + P miR-125b NM_003011 SET SET translocation (myeloid M + T DNA replication|endoplasmic leukemia-associated) reticulum|histone binding|negative regulation of histone acetylation|nucleocytoplasmic transport|nucleosome assembly|nucleosome disassembly|nucleus|perinuclear region|protein phosphatase inhibitor activity|protein phosphatase type 2A regulator activity miR-125b NM_006275 SFRS6 splicing factor, P + T RNA binding|mRNA splice site arginine/serine-rich 6 selection|nuclear mRNA splicing, via spliceosome|nucleotide binding|nucleus miR-125b AF015043 SH3BP4 SH3-domain binding protein 4 P + T cell cycle|endocytosis|nucleus|signal transducer activity miR-125b NM_016538 SIRT7 sirtuin silent mating type P + T DNA binding|chromatin information regulation 2 silencing|chromatin silencing homolog 7 (S. cerevisiae) complex|hydrolase activity|regulation of transcription, DNA-dependent miR-125b NM_020309 SLC17A7 solute carrier family 17 P + T integral to membrane|phosphate (sodium-dependent transport|sodium-dependent inorganic phosphate phosphate transporter cotransporter), member 7 activity|transport|transporter activity miR-125b NM_013272 SLC21A11 solute carrier family 21 P + T integral to membrane|ion (organic anion transporter), transport|membrane|transporter member 11 activity miR-125b AK000722 SLC27A4 solute carrier family 27 P + T catalytic activity|fatty acid (fatty acid transporter), transport|fatty acid transporter member 4 activity|ligase activity|lipid metabolism|lipid transport|metabolism miR-125b NM_003759 SLC4A4 solute carrier family 4, P + T anion transport|inorganic anion sodium bicarbonate exchanger activity|integral to cotransporter, member 4 membrane|integral to plasma membrane|membrane|sodium:bicarbonate symporter activity|transport miR-125b NM_003045 SLC7A1 solute carrier family 7 P + T amino acid metabolism|amino acid (cationic amino acid permease activity|amino acid transporter, y+ system), transport|basic amino acid member 1 transporter activity|integral to plasma membrane|membrane|receptor activity|transport miR-125b NM_003983 SLC7A6 solute carrier family 7 P + T amino acid metabolism|amino acid (cationic amino acid transport|amino acid-polyamine transporter, y+ system), transporter activity|integral to plasma member 6 membrane|plasma membrane|protein complex assembly|transport miR-125b AF113019 SMARCD2 SWI/SNF related, matrix M + P + T chromatin associated, actin dependent remodeling|nucleoplasm|regulation regulator of chromatin, of transcription from RNA subfamily d, member 2 polymerase II promoter|transcription|transcription coactivator activity miR-125b NM_005985 SNAI1 snail homolog 1 P + T DNA binding|cartilage (Drosophila) condensation|development|neuro- genesis|nucleus|zinc ion binding miR-125b AB037750 SORCS2 VPS10 domain receptor P + T integral to membrane|intracellular protein protein transport|membrane|membrane|neuropeptide receptor activity|neuropeptide signaling pathway|protein binding|protein transporter activity|sugar binding miR-125b BE742268 SORT1 sortilin 1 P + T endocytosis|endosome|integral to membrane|integral to membrane|intracellular protein transport|membrane|neurotensin receptor activity, G-protein coupled|protein transporter activity|receptor activity miR-125b AI360875 SOX11 SRY (sex determining M + T DNA region Y)-box 11 binding|neurogenesis|nucleus|regulation of transcription, DNA- dependent|transcription miR-125b AU121035 SP1 Sp1 transcription factor P + T DNA binding|RNA polymerase II transcription factor activity|nucleus|regulation of transcription, DNA- dependent|transcription|transcriptional activator activity|zinc ion binding miR-125b NM_003131 SRF serum response factor (c-fos M + T RNA polymerase II transcription serum response element factor activity|nucleus|regulation of binding transcription factor) transcription from RNA polymerase II promoter|signal transduction|transcription|transcription factor activity miR-125b NM_005637 SS18 synovial sarcoma P + T nucleus translocation, chromosome 18 miR-125b AF343880 SSX2 synovial sarcoma, X P + T nucleus breakpoint 2 miR-125b NM_014682 ST18 suppression of P + T nucleus|regulation of transcription, tumorigenicity 18 (breast DNA-dependent|transcription factor carcinoma) (zinc finger activity protein) miR-125b AA128023 STARD13 START domain containing 13 P + T miR-125b BC000627 STAT3 signal transducer and P + T JAK-STAT cascade|acute-phase activator of transcription 3 response|calcium ion binding|cell (acute-phase response motility|cytoplasm|hematopoietin|interferon- factor) class (D200-domain) cytokine receptor signal transducer activity|intracellular signaling cascade|negative regulation of transcription from RNA polymerase II promoter|neurogenesis|nucleus|nu- cleus|regulation of transcription, DNA- dependent|signal transducer activity|transcription|transcription factor activity|transcription factor activity miR-125b NM_003155 STC1 stanniocalcin 1 P + T calcium ion homeostasis|cell surface receptor linked signal transduction|cell-cell signaling|extracellular region|hormone activity|response to nutrients miR-125b NM_003173 SUV39H1 suppressor of variegation 3- P + T DNA replication and chromosome 9 homolog 1 (Drosophila) cycle|S-adenosylmethionine- dependent methyltransferase activity|chromatin|chromatin assembly or disassembly|chromatin binding|chromatin modification|condensed nuclear chromosome|histone lysine N- methyltransferase activity (H3-K9 specific)|histone-lysine N- methyltransferase activity|methyltransferase activity|nucleus|nucleus|protein binding|transferase activity|zinc ion binding miR-125b AW139618 SYN2 synapsin II P + T neurotransmitter secretion|synapse|synaptic transmission|synaptic vesicle miR-125b R60550 TAF5L TAF5-like RNA polymerase M + P + T nucleus|regulation of transcription, II, p300/CBP-associated DNA-dependent|transcription factor factor (PCAF)-associated activity|transcription from RNA factor, 65 kDa polymerase II promoter miR-125b AF220509 TAF9L TAF9-like RNA polymerase P + T DNA binding|nucleus|regulation of II, TATA box binding transcription, DNA- protein (TBP)-associated dependent|transcription factor TFIID factor, 31 kDa complex|transcription initiation miR-125b NM_000116 TAZ tafazzin (cardiomyopathy, M + P + T acyltransferase activity|heart dilated 3A (X-linked); development|integral to endocardial fibroelastosis 2; membrane|metabolism|muscle Barth syndrome) contraction|muscle development miR-125b NM_018488 TBX4 T-box 4 P + T development|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity miR-125b NM_012249 TC10 ras-like protein TC10 M + T GTP binding|GTPase activity|plasma membrane|small GTPase mediated signal transduction miR-125b BG387172 TEAD2 TEA domain family P + T nucleus|nucleus|regulation of member 2 transcription, DNA- dependent|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcription factor activity miR-125b U06935 TEF thyrotrophic embryonic P + T RNA polymerase II transcription factor factor activity|nucleus|regulation of transcription from RNA polymerase II promoter|rhythmic process|transcription|transcription factor activity miR-125b NM_006464 TGOLN2 trans-golgi network protein 2 P + T Golgi trans face|integral to membrane|transport vesicle miR-125b BE219311 TIMM22 translocase of inner P + T integral to membrane|mitochondrial mitochondrial membrane 22 inner homolog (yeast) membrane|mitochondrion|protein transport|protein transporter activity miR-125b NM_003326 TNFSF4 tumor necrosis factor P + T cell-cell signaling|immune (ligand) superfamily, response|integral to plasma member 4 (tax- membrane|membrane|positive transcriptionally activated regulation of cell proliferation|signal glycoprotein 1, 34 kDa) transduction|tumor necrosis factor receptor binding miR-125b AA873275 TOR2A torsin family 2, member A P + T ATP binding|GTP cyclohydrolase I activity|biosynthesis|chaperone cofactor dependent protein folding|endoplasmic reticulum|nucleoside-triphosphatase activity|nucleotide binding miR-125b AW341649 TP53INP1 tumor protein p53 inducible M + P + T apoptosis|nucleus nuclear protein 1 miR-125b NM_014112 TRPS1 trichorhinophalangeal P + T NLS-bearing substrate-nucleus syndrome I import|nucleus|regulation of transcription, DNA- dependent|skeletal development|transcription|transcription factor activity|transcription from RNA polymerase II promoter|zinc ion binding miR-125b NM_001070 TUBG1 tubulin, gamma 1 P + T GTP binding|GTPase activity|centrosome|condensed nuclear chromosome|gamma-tubulin complex|meiotic spindle organization and biogenesis|microtubule|microtubule nucleation|microtubule-based movement|mitotic spindle organization and biogenesis|polar microtubule|protein binding|protein polymerization|spindle pole body|structural constituent of cytoskeleton miR-125b NM_003330 TXNRD1 thioredoxin reductase 1 P + T FAD binding|cell redox homeostasis|cytoplasm|disulfide oxidoreductase activity|electron transport|electron transporter activity|oxidoreductase activity, acting on NADH or NADPH, disulfide as acceptor|signal transduction|thioredoxin-disulfide reductase activity miR-125b BC004862 UBE2R2 ubiquitin-conjugating P + T ligase activity|ubiquitin conjugating enzyme E2R 2 enzyme activity|ubiquitin cycle|ubiquitin-protein ligase activity miR-125b NM_003728 UNC5C unc-5 homolog B P + T apoptosis|axon guidance|brain (C. elegans) development|development|integral to membrane|netrin receptor activity|protein binding|receptor activity|signal transduction miR-125b NM_003369 UVRAG UV radiation resistance P + T DNA repair|cytoplasm associated gene miR-125b AF195514 VPS4B vacuolar protein sorting 4B M + P + T ATP binding|ATPase activity, (yeast) coupled|membrane|membrane fusion|nucleoside-triphosphatase activity|nucleotide binding|peroxisome organization and biogenesis|protein binding|regulation of transcription, DNA-dependent miR-125b R51061 VTS58635 mitogen-activated protein P + T GTP binding|small GTPase mediated kinase kinase kinase kinase 1 signal transduction miR-125b NM_004184 WARS tryptophanyl-tRNA M + T ATP binding|cytoplasm|ligase synthetase activity|negative regulation of cell proliferation|protein biosynthesis|soluble fraction|tryptophan-tRNA ligase activity|tryptophanyl-tRNA aminoacylation|tryptophanyl-tRNA aminoacylation miR-125b NM_005433 YES1 v-yes-1 Yamaguchi sarcoma P + T ATP binding|intracellular signaling viral oncogene homolog 1 cascade|protein amino acid phosphorylation|protein-tyrosine kinase activity|transferase activity miR-125b NM_017740 ZDHHC7 zinc finger, DHHC domain P + T integral to membrane|metal ion containing 7 binding miR-125b BF525395 ZFP385 likely ortholog of mouse M + P + T DNA binding|nucleic acid zinc finger protein 385 binding|nucleus|regulation of transcription, DNA- dependent|transcription|zinc ion binding miR-125b NM_007345 ZNF236 zinc finger protein 236 P + T nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity|zinc ion binding miR-125b NM_012482 ZNF281 zinc finger protein 281 M + P + T DNA binding|DNA-directed RNA polymerase II, core complex|negative regulation of transcription from RNA polymerase II promoter|nucleus|regulation of transcription, DNA- dependent|specific RNA polymerase II transcription factor activity|transcription|zinc ion binding miR-125b NM_003427 ZNF76 zinc finger protein 76 P + T DNA binding|nucleus|regulation of (expressed in testis) transcription from RNA polymerase II promoter|regulation of transcription from RNA polymerase III promoter|transcription|zinc ion binding miR-125b NM_022465 ZNFN1A4 zinc finger protein, M + P + T nucleic acid subfamily 1A, 4 (Eos) binding|nucleus|transcription factor activity|transcriptional repressor activity|zinc ion binding miR-145 NM_005502 ABCA1 ATP-binding cassette, sub- P + T ATP binding|ATP binding|ATPase family A (ABC1), member 1 activity|anion transporter activity|cholesterol metabolism|integral to plasma membrane|lipid metabolism|membrane fraction|nucleotide binding|steroid metabolism|sterol transporter activity|transport|transport miR-145 AL527773 ABR active BCR-related gene M + P + T GTPase activator activity|guanyl- nucleotide exchange factor activity|small GTPase mediated signal transduction miR-145 NM_001616 ACVR2 activin A receptor, type II M + P + T ATP binding|integral to plasma membrane|membrane|protein amino acid phosphorylation|receptor activity|transferase activity|transforming growth factor beta receptor activity|transmembrane receptor protein serine/threonine kinase signaling pathway miR-145 NM_003183 ADAM17 a disintegrin and P + T cell-cell signaling|integral to plasma metalloproteinase domain membrane|metalloendopeptidase 17 (tumor necrosis factor, activity|proteolysis and alpha, converting enzyme) peptidolysis|zinc ion binding miR-145 NM_019903 ADD3 adducin 3 (gamma) M + P + T calmodulin binding|cytoskeleton|membrane|structural constituent of cytoskeleton miR-145 AB003476 AKAP12 A kinase (PRKA) anchor P + T G-protein coupled receptor protein protein (gravin) 12 signaling pathway|cytoplasm|protein binding|protein kinase A binding|protein targeting|signal transduction miR-145 NM_016201 AMOTL2 angiomotin like 2 M + P + T miR-145 NM_001128 AP1G1 adaptor-related protein M + P + T Golgi apparatus|binding|clathrin coat complex 1, gamma 1 subunit of trans-Golgi network vesicle|coated pit|endocytosis|intracellular protein transport|intracellular protein transport|membrane coat adaptor complex|protein complex assembly|transporter activity miR-145 NM_001284 AP3S1 adaptor-related protein M + P + T Golgi apparatus|clathrin vesicle complex 3, sigma 1 subunit coat|insulin receptor signaling pathway|intracellular protein transport|membrane coat adaptor complex|transport|transport vesicle|transporter activity miR-145 NM_006380 APPBP2 amyloid beta precursor M + P + T binding|cytoplasm|intracellular protein (cytoplasmic tail) protein binding protein 2 transport|membrane|microtubule associated complex|microtubule motor activity|nucleus miR-145 AB037845 ARHGAP10 Rho-GTPase activating M + T protein binding protein 10 miR-145 AL516350 ARPC5 actin related protein 2/3 P + T Arp2/3 protein complex|actin complex, subunit 5, 16 kDa cytoskeleton organization and biogenesis|cell motility|cytoplasm|cytoskeleton|regulation of actin filament polymerization|structural constituent of cytoskeleton miR-145 U72937 ATRX alpha thalassemia/mental M + T ATP binding|DNA binding|DNA retardation syndrome X- helicase activity|DNA linked (RAD54 homolog, methylation|DNA S. cerevisiae) recombination|DNA repair|chromosome organization and biogenesis (sensu Eukaryota)|helicase activity|hydrolase activity|nuclear heterochromatin|nucleus|perception of sound|regulation of transcription, DNA-dependent|transcription factor activity miR-145 NM_021813 BACH2 BTB and CNC homology 1, P + T DNA binding|nucleus|protein basic leucine zipper binding|regulation of transcription, transcription factor 2 DNA-dependent|transcription miR-145 NM_013449 BAZ2A bromodomain adjacent to P + T DNA binding|chromatin zinc finger domain, 2A remodeling|nucleolus organizer complex|nucleus|regulation of transcription, DNA- dependent|transcription|transcription regulator activity miR-145 NM_007005 BCE-1 BCE-1 protein M + P frizzled signaling pathway|molecular_function unknown|nucleus|nucleus|regulation of transcription|regulation of transcription, DNA-dependent miR-145 NM_003458 BSN bassoon (presynaptic P + T cytoskeleton|metal ion cytomatrix protein) binding|nucleus|structural constituent of cytoskeleton|synapse|synaptic transmission|synaptosome miR-145 NM_013279 C11orf9 chromosome 11 open M + P + T reading frame 9 miR-145 NM_024643 C14orf140 hypothetical protein P + T FLJ23093 miR-145 NM_018270 C20orf20 chromosome 20 open P + T chromatin reading frame 20 modification|nucleus|regulation of cell growth|regulation of transcription, DNA- dependent|transcription miR-145 NM_004276 CABP1 calcium binding protein 1 P + T calcium ion binding|calcium ion (calbrain) binding|enzyme inhibitor activity miR-145 NM_001755 CBFB core-binding factor, beta M + P + T RNA polymerase II transcription subunit factor activity|nucleus|transcription coactivator activity|transcription factor activity|transcription from RNA polymerase II promoter miR-145 NM_001759 CCND2 cyclin D2 P + T cytokinesis|nucleus|regulation of cell cycle miR-145 NM_020307 CCNL1 cyclin L ania-6a M + P + T cell cycle|regulation of cell cycle miR-145 AL118798 CD47 CD47 antigen (Rh-related P + T cell-matrix adhesion|integral to antigen, integrin-associated plasma membrane|integrin-mediated signal transducer) signaling pathway|plasma membrane|protein binding miR-145 BF576053 CFL2 cofilin 2 (muscle) M + P + T actin binding|cytoskeleton|nucleus miR-145 AA835485 CKLiK CamKI-like protein kinase P + T ATP binding|calcium- and calmodulin-dependent protein kinase activity|calmodulin binding|nucleus|protein amino acid phosphorylation|protein serine/threonine kinase activity|transferase activity miR-145 NM_004921 CLCA3 chloride channel, calcium P + T extracellular activated, family member 3 space|transport|transporter activity miR-145 NM_001326 CSTF3 cleavage stimulation factor, M + P + T RNA binding|binding|mRNA 3′ pre-RNA, subunit 3, cleavage|mRNA 77 kDa polyadenylylation|nucleus miR-145 NM_020248 CTNNBIP1 catenin, beta interacting P + T Wnt receptor signaling pathway|beta- protein 1 catenin binding|cell proliferation|development|nucleus|regulation of transcription, DNA- dependent|signal transduction miR-145 AW772082 DACH dachshund homolog P + T DNA binding|development|eye (Drosophila) morphogenesis (sensu Endopterygota)|nucleus|regulation of transcription, DNA- dependent|transcription miR-145 NM_004393 DAG1 dystroglycan 1 (dystrophin- M + P + T actin cytoskeleton|calcium ion associated glycoprotein 1) binding|extracellular matrix (sensu Metazoa)|integral to plasma membrane|laminin receptor activity|membrane fraction|muscle contraction|plasma membrane|protein binding|protein complex assembly miR-145 NM_003887 DDEF2 development and P + T GTPase activator activity|Golgi differentiation enhancing apparatus|regulation of GTPase factor 2 activity miR-145 AL080239 DKFZp547M2010 hypothetical protein M + P + T DKFZp547M2010 miR-145 AL137517 DKFZp564O1278 hypothetical protein P + T integral to membrane DKFZp564O1278 miR-145 NM_001386 DPYSL2 dihydropyrimidinase-like 2 P + T dihydropyrimidinase activity|hydrolase activity|neurogenesis|nucleobase, nucleoside, nucleotide and nucleic acid metabolism|signal transduction miR-145 BC003143 DUSP6 dual specificity phosphatase 6 P + T MAP kinase phosphatase activity|cytoplasm|hydrolase activity|inactivation of MAPK|protein amino acid dephosphorylation|protein serine/threonine phosphatase activity|protein tyrosine phosphatase activity|regulation of cell cycle|soluble fraction miR-145 D86550 DYRK1A dual-specificity tyrosine- P + T ATP (Y)-phosphorylation binding|neurogenesis|nucleus|protein regulated kinase 1A amino acid phosphorylation|protein serine/threonine kinase activity|protein-tyrosine kinase activity|transferase activity miR-145 NM_001967 EIF4A2 eukaryotic translation M + P + T ATP binding|ATP-dependent initiation factor 4A, isoform 2 helicase activity|DNA binding|RNA binding|eukaryotic translation initiation factor 4F complex|hydrolase activity|protein biosynthesis|regulation of translational initiation|translation initiation factor activity miR-145 NM_001417 EIF4B eukaryotic translation M + T RNA binding|eukaryotic translation initiation factor 4B initiation factor 4F complex|nucleic acid binding|nucleotide binding|protein biosynthesis|regulation of translational initiation|translation initiation factor activity|translation initiation factor activity miR-145 BC005057 EIF4EBP2 eukaryotic translation P + T eukaryotic initiation factor 4E initiation factor 4E binding binding|negative regulation of protein 2 protein biosynthesis|negative regulation of translational initiation|regulation of translation miR-145 NM_020909 EPB41L5 erythrocyte membrane P + T binding|cytoplasm|cytoskeletal protein band 4.1 like 5 protein binding|cytoskeleton|membrane miR-145 NM_005797 EVA1 epithelial V-like antigen 1 P + T cell adhesion|cytoskeleton|homophilic cell adhesion|integral to membrane|membrane|morpho- genesis|protein binding miR-145 NM_022977 FACL4 fatty-acid-Coenzyme A M + P + T fatty acid metabolism|integral to ligase, long-chain 4 membrane|learning and/or memory|ligase activity|lipid metabolism|long-chain-fatty-acid- CoA ligase activity|magnesium ion binding|metabolism miR-145 AL042120 FHOD2 formin homology 2 domain M + P Rho GTPase binding|actin containing 2 binding|actin cytoskeleton organization and biogenesis|cell organization and biogenesis|nucleus|regulation of transcription, DNA- dependent|transcription factor activity|translation initiation factor activity|translational initiation miR-145 NM_002013 FKBP3 FK506 binding protein 3, P + T FK506 binding|isomerase 25 kDa activity|nucleus|peptidyl-prolyl cis- trans isomerase activity|protein folding|receptor activity miR-145 NM_002017 FLI1 Friend leukemia virus M + P + T hemostasis|nucleus|organogenesis|regulation integration 1 of transcription, DNA- dependent|transcription|transcription factor activity miR-145 NM_023071 FLJ13117 hypothetical protein P + T FLJ13117 miR-145 AL561281 FLJ20373 hypothetical protein M + P + T ATP binding|cellular_component FLJ20373 unknown|protein amino acid phosphorylation|protein kinase cascade|protein serine/threonine kinase activity|response to stress|signal transduction|small GTPase regulator activity|transferase activity miR-145 AK025444 FLJ21791 hypothetical protein M + T FLJ21791 miR-145 NM_024713 FLJ22557 hypothetical protein P + T FLJ22557 miR-145 AA872588 FLJ36155 likely ortholog of mouse P + T DNA binding|negative regulation of Gli-similar 1 Kruppel-like transcription from RNA polymerase zinc finger (Glis1) II promoter|nucleus|positive regulation of transcription from RNA polymerase II promoter|regulation of transcription, DNA- dependent|specific RNA polymerase II transcription factor activity|transcription|zinc ion binding miR-145 AI434509 FLJ38499 Unnamed protein product P + T nucleic acid binding [Homo sapiens], mRNA sequence miR-145 M62994 FLNB filamin B, beta (actin P + T actin binding|actin binding|actin binding protein 278) cytoskeleton|actin cytoskeleton organization and biogenesis|cell differentiation|cytoskeletal anchoring|integral to plasma membrane|myogenesis|signal transduction miR-145 NM_002025 FMR2 fragile X mental retardation 2 M + T brain development|learning and/or memory miR-145 N29672 FOS v-fos FBJ murine M + T proto-oncogene osteosarcoma viral oncogene homolog miR-145 NM_002015 FOXO1A forkhead box O1A M + P + T anti-apoptosis|nucleus|regulation of (rhabdomyosarcoma) transcription from RNA polymerase II promoter|transcription|transcription factor activity miR-145 NM_003507 FZD7 frizzled homolog 7 M + P + T G-protein coupled receptor (Drosophila) activity|G-protein coupled receptor protein signaling pathway|Wnt receptor activity|development|frizzled signaling pathway|integral to membrane|plasma membrane miR-145 AL049709 GGTL3 gamma-glutamyltransferase- M + P + T like 3 miR-145 NM_022735 GOCAP1 golgi complex associated M + P + T Golgi apparatus|acyl-CoA protein 1, 60 kDa binding|catalytic activity|intracellular protein transport|membrane|mitochondrion|protein carrier activity|steroid biosynthesis miR-145 NM_020806 GPHN gephyrin P + T Mo-molybdopterin cofactor biosynthesis|catalytic activity|cytoskeleton miR-145 NM_015071 GRAF GTPase regulator associated P + T Rho GTPase activator activity|actin with focal adhesion kinase cytoskeleton organization and pp125(FAK) biogenesis|cellular_component unknown|neurogenesis miR-145 NM_017913 HARC Hsp90-associating relative P + T cytokinesis|regulation of cell cycle of Cdc37 miR-145 BC006237 HECTD1 HECT domain containing 1 M + T intracellular|ligase activity|receptor activity|ubiquitin cycle|ubiquitin- protein ligase activity miR-145 U64317 HEF1 enhancer of filamentation 1 P + T actin filament bundle formation|cell (cas-like docking; Crk- adhesion|cytokinesis|cytoplasm|cyto- associated substrate related) skeleton|cytoskeleton organization and biogenesis|integrin-mediated signaling pathway|mitosis|nucleus|protein binding|regulation of cell cycle|regulation of cell growth|signal transduction|spindle miR-145 NM_016258 HGRG8 high-glucose-regulated P + T protein 8 miR-145 AL162003 HIC2 hypermethylated in cancer 2 P + T DNA binding|negative regulation of transcription, DNA- dependent|nucleus|protein C- terminus binding|transcription|zinc ion binding miR-145 NM_014212 HOXC11 homeo box C11 M + P + T RNA polymerase II transcription factor activity|development|endoderm development|nucleus|regulation of transcription, DNA- dependent|transcription factor activity miR-145 NM_002193 INHBB inhibin, beta B (activin AB M + P + T cell differentiation|cytokine beta polypeptide) activity|defense response|extracellular region|growth|growth factor activity hormone activity|host cell surface receptor binding|negative regulation of follicle-stimulating hormone secretion|negative regulation of hepatocyte growth factor biosynthesis|ovarian follicle development|positive regulation of follicle-stimulating hormone secretion|protein binding|protein homodimerization activity|response to external stimulus miR-145 NM_005544 IRS1 insulin receptor substrate 1 M + P + T cytoplasm|insulin receptor binding|protein binding|signal transducer activity|signal transduction|transmembrane receptor protein tyrosine kinase docking protein activity miR-145 NM_006459 KEO4 similar to Caenorhabditis P + T catalytic activity elegans protein C42C1.9 miR-145 NM_014686 KIAA0355 KIAA0355 gene product P + T miR-145 NM_015176 KIAA0483 KIAA0483 protein P + T ubiquitin cycle miR-145 NM_014871 KIAA0710 KIAA0710 gene product M + P + T cysteine-type endopeptidase activity|exonuclease activity|nucleus|ubiquitin cycle|ubiquitin thiolesterase activity|ubiquitin-dependent protein catabolism miR-145 AA772278 KIAA1673 KIAA1673 M + P + T miR-145 AB051495 KIAA1708 KIAA1708 protein P + T ATP binding|microtubule associated complex|microtubule motor activity|microtubule-based movement miR-145 AI814587 KIAA1715 KIAA1715 protein M + T miR-145 AI187364 KIAA1894 KIAA1894 protein P + T integral to membrane miR-145 AF155117 KIF21A kinesin family member 21A P + T ATP binding|microtubule associated complex|microtubule motor activity|microtubule-based movement miR-145 NM_004235 KLF4 Kruppel-like factor 4 (gut) M + T mesodermal cell fate determination|negative regulation of cell proliferation|negative regulation of transcription, DNA- dependent|negative regulation of transcription, DNA- dependent|nucleic acid binding|nucleus|transcription|transcription factor activity|transcription factor activity|transcriptional activator activity|transcriptional activator activity|transcriptional repressor activity|transcriptional repressor activity|zinc ion binding|zinc ion binding miR-145 T68150 LL5beta hypothetical protein M + T FLJ21791 miR-145 AI797833 LOC285148 a disintegrin and P + T catalytic activity metalloproteinase domain 17 (tumor necrosis factor, alpha, converting enzyme) miR-145 NM_025146 MAK3P likely ortholog of mouse P + T N-acetyltransferase activity Mak3p homolog (S. cerevisiae) miR-145 BF971923 MAP3K3 mitogen-activated protein M + P ATP binding|MAP kinase kinase kinase kinase kinase 3 kinase activity|MAPKKK cascade|magnesium ion binding|positive regulation of I- kappaB kinase/NF-kappaB cascade|protein amino acid phosphorylation|protein kinase activity|protein serine/threonine kinase activity|signal transducer activity|transferase activity miR-145 NM_004834 MAP4K4 mitogen-activated protein M + P + T ATP binding|cellular_component kinase kinase kinase kinase 4 unknown|protein amino acid phosphorylation|protein kinase cascade|protein serine/threonine kinase activity|response to stress|signal transduction|small GTPase regulator activity|transferase activity miR-145 BF382281 MGC10120 Homo sapiens cDNA P + T FLJ30135 fis, clone BRACE2000061, mRNA sequence miR-145 BG231756 MGC10986 hypothetical protein M + P ATP binding|MAP kinase kinase MGC10986 kinase activity|MAPKKK cascade|magnesium ion binding|positive regulation of I- kappaB kinase/NF-kappaB cascade|protein amino acid phosphorylation|protein kinase activity|protein serine/threonine kinase activity|signal transducer activity|transferase activity miR-145 BC004869 MGC2817 hypothetical protein P + T outer membrane|protein transport MGC2817 miR-145 BC002712 MYCN v-myc myelocytomatosis M + T chromatin|nucleus|protein viral related oncogene, binding|regulation of transcription neuroblastoma derived from RNA polymerase II (avian) promoter|transcription factor activity miR-145 AB007899 NEDD4L neural precursor cell P + T excretion|intracellular|intracellular|ligase expressed, developmentally activity|positive regulation of down-regulated 4-like endocytosis|protein binding|protein ubiquitination|regulation of protein catabolism|response to metal ion|sodium channel regulator activity|sodium ion homeostasis|sodium ion transport|ubiquitin cycle|ubiquitin- protein ligase activity|ubiquitin- protein ligase activity|water homeostasis miR-145 NM_005863 NET1 neuroepithelial cell P + T guanyl-nucleotide exchange factor transforming gene 1 activity|nucleus|regulation of cell growth|signal transduction miR-145 NM_003204 NFE2L1 nuclear factor (erythroid- P + T DNA binding|heme derived 2)-like 1 biosynthesis|inflammatory response|morphogenesis|nucleus|nu- cleus|regulation of transcription, DNA- dependent|transcription|transcription cofactor activity|transcription factor activity|transcription from RNA polymerase II promoter miR-145 NM_006469 NS1-BP NS1-binding protein M + P + T RNA splicing|protein binding|response to virus|spliceosome complex|transcription factor complex|transcription from RNA polymerase III promoter miR-145 NM_019094 NUDT4 nudix (nucleoside P + T calcium-mediated signaling/cyclic diphosphate linked moiety nucleotide metabolism cyclic- X)-type motif 4 nucleotide-mediated signaling|diphosphoinositol- polyphosphate diphosphatase activity|hydrolase activity|intracellular|intracellular signaling cascade|intracellular transport|magnesium ion binding|regulation of RNA-nucleus export miR-145 AW149417 OAZ OLF-1/EBF associated zinc P + T nucleic acid binding|nucleus|zinc ion finger gene binding miR-145 NM_024586 OSBPL9 oxysterol binding protein- M + P lipid transport|steroid metabolism like 9 miR-145 AB040812 PAK7 p21(CDKN1A)-activated M + T ATP binding protein amino acid kinase 7 phosphorylation|protein serine/threonine kinase activity|transferase activity miR-145 NM_014456 PDCD4 programmed cell death 4 M + P + T apoptosis (neoplastic transformation inhibitor) miR-145 NM_002657 PLAGL2 pleiomorphic adenoma M + P + T nucleus|regulation of transcription, gene-like 2 DNA- dependent|transcription|transcription factor activity|zinc ion binding miR-145 AK023546 PLCL2 phospholipase C-like 2 P + T calcium ion binding|intracellular signaling cascade|lipid metabolism|phosphoinositide phospholipase C activity miR-145 AI274352 PLN phospholamban P + T miR-145 NM_000944 PPP3CA protein phosphatase 3 P + T calcineurin complex|calcium ion (formerly 2B), catalytic binding|calmodulin subunit, alpha isoform binding|hydrolase activity|protein (calcineurin A alpha) amino acid dephosphorylation|protein serine/threonine phosphatase activity miR-145 BF247371 PRO1843 hypothetical protein M + T PRO1843 miR-145 NM_000959 PTGFR prostaglandin F receptor P + T G-protein coupled receptor protein (FP) signaling pathway|G-protein coupled receptor protein signaling pathway|integral to membrane|integral to plasma membrane|parturition|prostaglandin F receptor activity|prostaglandin F receptor activity|receptor activity|rhodopsin-like receptor activity|signal transduction|thromboxane receptor activity miR-145 NM_002890 RASA1 RAS p21 protein activator P + T Ras GTPase activator (GTPase activating protein) 1 activity|intracellular signaling cascade miR-145 NM_006506 RASA2 RAS p21 protein activator 2 P + T Ras GTPase activator activity|intracellular signaling cascade miR-145 NM_002912 REV3L REV3-like, catalytic subunit M + P + T 3′-5′ exonuclease activity|DNA of DNA polymerase zeta binding|DNA repair|DNA (yeast) replication|DNA-dependent DNA replication|DNA-directed DNA polymerase activity|nucleotide binding|nucleus|transferase activity|zeta DNA polymerase activity|zeta DNA polymerase complex miR-145 NM_002924 RGS7 regulator of G-protein P + T heterotrimeric G-protein signalling 7 complex|intracellular signaling cascade|regulation of G-protein coupled receptor protein signaling pathway|regulator of G-protein signaling activity|signal transducer activity miR-145 AL136924 RIN2 Ras and Rab interactor 2 P + T GTPase activator activity|Rab guanyl-nucleotide exchange factor activity|cellular_component unknown|endocytosis|intracellular signaling cascade|small GTPase mediated signal transduction|small GTPase regulator activity miR-145 BE463945 RTKN rhotekin P + T intracellular|protein binding|signal transduction|signal transduction miR-145 AF225986 SCN3A sodium channel, voltage- P + T cation channel activity|cation gated, type III, alpha transport|integral to polypeptide membrane|membrane|sodium ion transport|voltage-gated sodium channel activity|voltage-gated sodium channel complex miR-145 NM_006080 SEMA3A sema domain, P + T cell differentiation|extracellular immunoglobulin domain region|neurogenesis (Ig), short basic domain, secreted, (semaphorin) 3A miR-145 NM_020796 SEMA6A sema domain, P + T apoptosis|axon|axon guidance|cell transmembrane domain differentiation|cell surface receptor (TM), and cytoplasmic linked signal domain, (semaphorin) 6A transduction|cytoskeleton organization and biogenesis|development|integral to membrane|membrane|neurogenesis|protein binding|receptor activity miR-145 NM_004171 SLC1A2 solute carrier family 1 (glial P + T L-glutamate transport|L-glutamate high affinity glutamate transporter activity|dicarboxylic acid transporter), member 2 transport|integral to membrane|membrane|membrane fraction|sodium:dicarboxylate symporter activity|symporter activity|synaptic transmission|transport miR-145 NM_003759 SLC4A4 solute carrier family 4, P + T anion transport|inorganic anion sodium bicarbonate exchanger activity|integral to cotransporter, member 4 membrane|integral to plasma membrane|membrane|sodium:bicarbonate symporter activity|transport miR-145 NM_030918 SNX27 hypothetical protein My014 M + P + T intracellular signaling cascade|protein binding|protein transport miR-145 AI360875 SOX11 SRY (sex determining M + T DNA region Y)-box 11 binding|neurogenesis|nucleus|regulation of transcription, DNA- dependent|transcription miR-145 NM_000346 SOX9 SRY (sex determining P + T DNA binding|cartilage region Y)-box 9 condensation|nucleus|regulation of (campomelic dysplasia, transcription from RNA polymerase autosomal sex-reversal) II promoter|skeletal development|specific RNA polymerase II transcription factor activity|transcription miR-145 AK023899 SRGAP1 SLIT-ROBO Rho GTPase P + T GTPase activator activity activating protein 1 miR-145 NM_003155 STC1 stanniocalcin 1 M + T calcium ion homeostasis|cell surface receptor linked signal transduction|cell-cell signaling|extracellular region|hormone activity|response to nutrients miR-145 BE219311 TIMM22 translocase of inner M + P + T integral to membrane|mitochondrial mitochondrial membrane 22 inner homolog (yeast) membrane|mitochondrion|protein transport|protein transporter activity miR-145 AA705845 TLE4 transducin-like enhancer of M + P frizzled signaling split 4 (E(sp1) homolog, pathway|molecular_function Drosophila) unknown|nucleus|nucleus|regulation of transcription|regulation of transcription, DNA-dependent miR-145 BC005016 TRIM2 tripartite motif-containing 2 P + T cytoplasm|myosin binding|protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-145 NM_025076 UXS1 UDP-glucuronate M + P + T carbohydrate metabolism|isomerase decarboxylase 1 activity|nucleotide-sugar metabolism miR-145 NM_005433 YES1 v-yes-1 Yamaguchi sarcoma P + T ATP binding|intracellular signaling viral oncogene homolog 1 cascade|protein amino acid phosphorylation|protein-tyrosine kinase activity|transferase activity miR-145 BC003128 ZDHHC9 zinc finger, DHHC domain P + T integral to membrane|metal ion containing 9 binding miR-155 NM_019903 ADD3 adducin 3 (gamma) P + T calmodulin binding|cytoskeleton|membrane|structural constituent of cytoskeleton miR-155 NM_020661 AICDA activation-induced cytidine P + T B-cell deaminase differentiation|cellular_component unknown|cytidine deaminase activity|hydrolase activity|mRNA processing|zinc ion binding miR-155 NM_007202 AKAP10 A kinase (PRKA) anchor P + T kinase activity|mitochondrion|protein protein 10 binding|protein localization|signal transducer activity|signal transduction miR-155 AI806395 ALFY ALFY P + T binding|zinc ion binding miR-155 NM_000038 APC adenomatosis polyposis coli P + T Wnt receptor signaling pathway|beta- catenin binding|cell adhesion|microtubule binding|negative regulation of cell cycle|protein|complex assembly|signal transduction miR-155 NM_017610 ARK Arkadia P + T protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-155 BG032269 ARL8 ADP-ribosylation-like factor 8 M + P + T GTP binding|small GTPase mediated signal transduction miR-155 AB000815 ARNTL aryl hydrocarbon receptor P + T circadian rhythm|nucleus|regulation nuclear translocator-like of transcription, DNA- dependent|signal transducer activity|signal transduction|transcription|transcription factor activity miR-155 NM_001670 ARVCF armadillo repeat gene P + T cell deletes in velocardiofacial adhesion|cytoskeleton|development|protein syndrome binding|structural molecule activity miR-155 AK024064 ASTN2 astrotactin 2 P + T integral to membrane miR-155 M95541 ATP2B1 ATPase, Ca++ transporting, M + P + T ATP binding|calcium ion plasma membrane 1 binding|calcium ion transport|calcium-transporting ATPase activity|calmodulin binding|cation transport|hydrolase activity|hydrolase activity, acting on acid anhydrides, catalyzing transmembrane movement of substances|integral to plasma membrane|magnesium ion binding|membrane|metabolism miR-155 NM_001186 BACH1 BTB and CNC homology 1, P + T DNA binding|nucleus|protein basic leucine zipper binding|regulation of transcription, transcription factor 1 DNA- dependent|transcription|transcription factor activity miR-155 NM_007005 BCE-1 BCE-1 protein P + T frizzled signaling pathway|molecular_function unknown|nucleus|nucleus|regulation of transcription|regulation of transcription, DNA-dependent miR-155 NM_022893 BCL11A B-cell CLL/lymphoma 11A P + T cytoplasm|hemopoiesis|nucleic acid (zinc finger protein) binding|nucleus|nucleus|regulation of transcription, DNA- dependent|transcription|zinc ion binding miR-155 NM_001709 BDNF brain-derived neurotrophic M + T growth factor activity|growth factor factor activity|neurogenesis miR-155 NM_014577 BRD1 bromodomain containing 1 P + T DNA binding|cell cycle|nucleus|nucleus|regulation of transcription, DNA-dependent miR-155 NM_024529 C1orf28 chromosome 1 open reading M + P + T frame 28 miR-155 NM_000719 CACNA1C calcium channel, voltage- P + T calcium ion binding|calcium ion dependent, L type, alpha 1C transport|cation transport|integral to subunit membrane|ion channel activity|ion transport|membrane|regulation of heart contraction rate|voltage-gated calcium channel activity|voltage- gated calcium channel activity|voltage-gated calcium channel complex|voltage-gated calcium channel complex miR-155 AL118798 CD47 CD47 antigen (Rh-related P + T cell-matrix adhesion|integral to antigen, integrin-associated plasma membrane|integrin-mediated signal transducer) signaling pathway|plasma membrane|protein binding miR-155 AL564683 CEBPB CCAAT/enhancer binding M + P + T acute-phase response|inflammatory protein (C/EBP), beta response|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcription from RNA polymerase II promoter miR-155 NM_007023 CGEF2 cAMP-regulated guanine M + P 3′,5′-cAMP binding|G-protein nucleotide exchange factor coupled receptor protein signaling II pathway|cAMP-dependent protein kinase complex|cAMP-dependent protein kinase regulator activity|exocytosis|guanyl-nucleotide exchange factor activity|membrane fraction|nucleotide binding|protein amino acid phosphorylation|small GTPase mediated signal transduction miR-155 AU152178 CMG2 capillary morphogenesis P + T integral to membrane|receptor protein 2 activity miR-155 NM_005776 CNIH cornichon homolog P + T immune response|integral to (Drosophila) membrane|intracellular signaling cascade|membrane miR-155 AW241703 CNTN4 Homo sapiens cDNA P + T cell adhesion|membrane|protein FLJ32716 fis, clone binding TESTI2000808, highly similar to Rattus norvegicus neural cell adhesion protein BIG-2 precursor (BIG-2) mRNA, mRNA sequence miR-155 NM_000094 COL7A1 collagen, type VII, alpha 1 P + T basement membrane|cell (epidermolysis bullosa, adhesion|collagen type dystrophic, dominant and VII|cytoplasm|epidermis recessive) development|phosphate transport|protein binding|serine-type endopeptidase inhibitor activity|structural molecule activity miR-155 NM_003653 COPS3 COP9 constitutive P + T signalosome complex photomorphogenic homolog subunit 3 (Arabidopsis) miR-155 NM_005211 CSF1R colony stimulating factor 1 M + P + T ATP binding|antimicrobial humoral receptor, formerly response (sensu Vertebrata)|cell McDonough feline sarcoma proliferation|development|integral to viral (v-fms) oncogene plasma membrane|macrophage homolog colony stimulating factor receptor activity|plasma membrane|protein amino acid phosphorylation|receptor activity|signal transduction|transferase activity|transmembrane receptor protein tyrosine kinase signaling pathway miR-155 NM_001892 CSNK1A1 casein kinase 1, alpha 1 P + T ATP binding|Wnt receptor signaling pathway|casein kinase I activity|protein amino acid phosphorylation|protein amino acid phosphorylation|protein serine/threonine kinase activity|protein-tyrosine kinase activity|transferase activity miR-155 NM_005214 CTLA4 cytotoxic T-lymphocyte- P + T immune response|immune associated protein 4 response|integral to plasma membrane|membrane miR-155 U69546 CUGBP2 CUG triplet repeat, RNA M + P + T RNA binding|RNA binding|RNA binding protein 2 processing|neuromuscular junction development|nucleotide binding|regulation of heart contraction rate miR-155 NM_030927 DC-TM4F2 tetraspanin similar to P + T integral to membrane TM4SF9 miR-155 NM_015652 DKFZP564P1916 DKFZP564P1916 protein P + T miR-155 AF151831 DKFZP566C134 DKFZP566C134 protein P + T protein binding miR-155 NM_004411 DNCI1 dynein, cytoplasmic, P + T cytoplasmic dynein complex|motor intermediate polypeptide 1 activity miR-155 NM_001400 EDG1 endothelial differentiation, P + T G-protein coupled receptor protein sphingolipid G-protein- signaling pathway|cell coupled receptor, 1 adhesion|integral to plasma membrane|lysosphingolipid and lysophosphatidic acid receptor activity|plasma membrane|receptor activity|signal transduction miR-155 NM_006795 EHD1 EH-domain containing 1 P + T ATP binding|GTP binding|GTPase activity|biological_process unknown|calcium ion binding|cellular_component unknown miR-155 NM_012081 ELL2 ELL-related RNA M + P + T RNA elongation from RNA polymerase II, elongation polymerase II promoter|RNA factor polymerase II transcription factor activity|nucleus|regulation of transcription, DNA- dependent|transcription|transcription elongation factor complex miR-155 NM_005238 ETS1 v-ets erythroblastosis virus P + T RNA polymerase II transcription E26 oncogene homolog 1 factor activity|immune (avian) response|negative regulation of cell proliferation|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcription from RNA polymerase II promoter miR-155 NM_002009 FGF7 fibroblast growth factor 7 P + T cell proliferation|cell-cell (keratinocyte growth factor) signaling|epidermis development|extracellular region|growth factor activity|positive regulation of cell proliferation|regulation of cell cycle|response to wounding|signal transduction miR-155 NM_018208 FLJ10761 hypothetical protein P + T biological_process FLJ10761 unknown|cellular_component unknown|choline kinase activity|transferase activity miR-155 NM_018243 FLJ10849 hypothetical protein P + T GTP binding|cell cycle|cytokinesis FLJ10849 miR-155 NM_022064 FLJ12565 hypothetical protein P + T ligase activity|protein FLJ12565 ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-155 NM_018391 FLJ23277 FLJ23277 protein P + T miR-155 NM_021078 GCN5L2 GCN5 general control of M + P + T N-acetyltransferase amino-acid synthesis 5-like activity|chromatin 2 (yeast) remodeling|histone acetyltransferase activity|histone deacetylase binding|nucleus|protein amino acid acetylation|regulation of transcription from RNA polymerase II promoter|transcription|transcription coactivator activity|transferase activity miR-155 NM_018178 GPP34R hypothetical protein P + T FLJ10687 miR-155 AF019214 HBP1 HMG-box containing M + P DNA binding|nucleus|regulation of protein 1 transcription, DNA-dependent miR-155 NM_006037 HDAC4 histone deacetylase 4 P + T B-cell differentiation|cell cycle|chromatin modification|cytoplasm|develop- ment|histone deacetylase activity|histone deacetylase complex|hydrolase activity|inflammatory response|negative regulation of myogenesis|neurogenesis|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor binding|transcriptional repressor activity miR-155 NM_001530 HIF1A hypoxia-inducible factor 1, P + T RNA polymerase II transcription alpha subunit (basic helix- factor activity, enhancer loop-helix transcription binding|electron transport|histone factor) acetyltransferase binding|homeostasis|nucleus|nu- cleus|protein heterodimerization activity|protein heterodimerization activity|regulation of transcription, DNA-dependent|response to hypoxia|signal transducer activity|signal transduction|signal transduction|transcription factor activity miR-155 AL023584 HIVEP2 human immunodeficiency P + T virus type I enhancer binding protein 2 miR-155 AI682088 HLCS holocarboxylase synthetase P + T biotin-[acetyl-CoA-carboxylase] (biotin-[proprionyl- ligase activity|biotin- Coenzyme A-carboxylase [methylcrotonoyl-CoA-carboxylase] (ATP-hydrolysing)] ligase) ligase activity|biotin- [methylmalonyl-CoA- carboxytransferase] ligase activity|biotin-[propionyl-CoA- carboxylase (ATP-hydrolyzing)] ligase activity|ligase activity|protein modification miR-155 NM_020190 HNOEL-iso HNOEL-iso protein P + T miR-155 NM_014002 IKBKE inhibitor of kappa light P + T ATP binding|NF-kappaB-inducing polypeptide gene enhancer kinase activity|cytoplasm|immune in B-cells, kinase epsilon response|positive regulation of I- kappaB kinase/NF-kappaB cascade|protein amino acid phosphorylation|protein serine/threonine kinase activity|signal transducer activity|transferase activity miR-155 D13720 ITK IL2-inducible T-cell kinase P + T ATP binding|cellular defense response|intracellular signaling cascade|non-membrane spanning protein tyrosine kinase activity|protein amino acid phosphorylation|transferase activity miR-155 NM_002249 KCNN3 potassium P + T calcium-activated potassium channel intermediate/small activity|calcium-activated potassium conductance calcium- channel activity|calmodulin activated channel, subfamily binding|integral to membrane|ion N, member 3 channel activity|ion transport|membrane|membrane fraction|neurogenesis|potassium ion transport|potassium ion transport|small conductance calcium- activated potassium channel activity|synaptic transmission|voltage-gated potassium channel complex miR-155 AB033100 KIAA1274 KIAA protein (similar to P + T protein tyrosine phosphatase activity mouse paladin) miR-155 NM_017780 KIAA1416 KIAA1416 protein P + T ATP binding|chromatin|chromatin assembly or disassembly|chromatin binding|helicase activity|nucleus miR-155 NM_002264 KPNA1 karyopherin alpha 1 P + T NLS-bearing substrate-nucleus (importin alpha 5) import|cytoplasm|intracellular protein transport|nuclear localization sequence binding|nuclear pore|nucleus|protein binding|protein transporter activity|regulation of DNA recombination miR-155 AK021602 KPNA4 karyopherin alpha 4 P + T NLS-bearing substrate-nucleus (importin alpha 3) import|binding|intracellular protein transport|nucleus|protein transporter activity miR-155 NM_020354 LALP1 lysosomal apyrase-like M + P + T hydrolase activity protein 1 miR-155 AW242408 LOC151531 Similar to uridine M + P + T cytosol|nucleoside phosphorylase metabolism|nucleotide [Homo sapiens], catabolism|protein mRNA sequence binding|transferase activity, transferring glycosyl groups|type III intermediate filament|uridine metabolism|uridine phosphorylase activity miR-155 NM_016210 LOC51161 g20 protein P + T miR-155 NM_018557 LRP1B low density lipoprotein- P + T calcium ion binding|integral to related protein 1B (deleted membrane|low-density lipoprotein in tumors) receptor activity|membrane|protein transport|receptor activity|receptor mediated endocytosis miR-155 NM_002446 MAP3K10 mitogen-activated protein M + P + T ATP binding|JUN kinase kinase kinase kinase kinase 10 kinase activity|activation of JNK|autophosphorylation|induction of apoptosis|protein homodimerization activity|protein serine/threonine kinase activity|protein-tyrosine kinase activity|signal transduction|transferase activity miR-155 NM_003954 MAP3K14 mitogen-activated protein P + T ATP binding|protein amino acid kinase kinase kinase 14 phosphorylation|protein serine/threonine kinase activity|transferase activity miR-155 AL117407 MAP3K7IP2 mitogen-activated protein P + T kinase activity|positive regulation of kinase kinase kinase 7 I-kappaB kinase/NF-kappaB interacting protein 2 cascade|positive regulation of I- kappaB kinase/NF-kappaB cascade|signal transducer activity|signal transducer activity miR-155 NM_004992 MECP2 methyl CpG binding protein M + P + T DNA binding|negative regulation of 2 (Rett syndrome) transcription from RNA polymerase II promoter|nucleus|regulation of transcription, DNA- dependent|transcription|transcription corepressor activity miR-155 NM_002398 MEIS1 Meis1, myeloid ecotropic M + P + T RNA polymerase II transcription viral integration site 1 factor activity|nucleus|regulation of homolog (mouse) transcription, DNA- dependent|transcription factor activity miR-155 NM_016289 MO25 MO25 protein P + T miR-155 AA621962 MYO1D myosin ID M + P + T ATP binding|actin binding|calmodulin binding|motor activity|myosin miR-155 NM_030571 N4WBP5 likely ortholog of mouse P + T positive regulation of I-kappaB Nedd4 WW binding protein 5 kinase/NF-kappaB cascade|signal transducer activity miR-155 NM_014903 NAV3 neuron navigator 3 P + T ATP binding|mitochondrion|nucleoside- triphosphatase activity|nucleotide binding miR-155 NM_030571 NDFIP1 likely ortholog of mouse P + T positive regulation of I-kappaB Nedd4 WW binding protein 5 kinase/NF-kappaB cascade|signal transducer activity miR-155 NM_006599 NFAT5 nuclear factor of activated M + P + T RNA polymerase II transcription T-cells 5, tonicity- factor responsive activity|excretion|nucleus|regulation of transcription, DNA- dependent|signal transduction|transcription factor activity|transcription from RNA polymerase II promoter miR-155 NM_002515 NOVA1 neuro-oncological ventral M + P + T RNA binding|RNA binding|RNA antigen 1 splicing|RNA splicing|locomotory behavior|locomotory behavior|nucleus|synaptic transmission|synaptic transmission miR-155 AI373299 PANK1 pantothenate kinase 1 P + T ATP binding|coenzyme A biosynthesis|pantothenate kinase activity|transferase activity miR-155 BG110231 PAPOLA poly(A) polymerase alpha P + T RNA binding|cytoplasm|mRNA polyadenylylation|mRNA processing|nucleus|polynucleotide adenylyltransferase activity|transcription|transferase activity miR-155 NM_020403 PCDH9 protocadherin 9 M + P + T calcium ion binding|cell adhesion|homophilic cell adhesion|integral to membrane|membrane|protein binding miR-155 NM_002655 PLAG1 pleiomorphic adenoma gene 1 P + T nucleic acid binding|nucleus|transcription factor activity|zinc ion binding miR-155 AJ272212 PSKH1 protein serine kinase H1 P + T ATP binding|Golgi apparatus|nucleus|protein amino acid phosphorylation|protein serine/threonine kinase activity|transferase activity miR-155 NM_014904 Rab11-FIP2 KIAA0941 protein P + T miR-155 AF322067 RAB34 RAB34, member RAS P + T GTP binding|Golgi apparatus|protein oncogene family transport|small GTPase mediated signal transduction miR-155 NM_002869 RAB6A RAB6A, member RAS M + P + T GTP binding|GTPase activity|Golgi oncogene family apparatus|protein transport|small GTPase mediated signal transduction miR-155 AL136727 RAB6C RAB6C, member RAS M + P + T GTP binding|GTPase oncogene family activity|intracellular|protein transport|response to drug|small GTPase mediated signal transduction miR-155 NM_002902 RCN2 reticulocalbin 2, EF-hand P + T calcium ion binding|endoplasmic calcium binding domain reticulum|protein binding miR-155 AJ223321 RP58 zinc finger protein 238 M + P + T miR-155 NM_002968 SALL1 sal-like 1 (Drosophila) P + T morphogenesis|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity|zinc ion binding miR-155 NM_002971 SATB1 special AT-rich sequence P + T double-stranded DNA binding protein 1 (binds to binding|establishment and/or nuclear matrix/scaffold- maintenance of chromatin associating DNA's) architecture|nucleus|regulation of transcription, DNA- dependent|transcription factor activity miR-155 NM_003469 SCG2 secretogranin II P + T calcium ion binding|protein secretion (chromogranin C) miR-155 NM_005625 SDCBP syndecan binding protein P + T actin cytoskeleton organization and (syntenin) biogenesis|adherens junction|cytoskeletal adaptor activity|cytoskeleton|endoplasmic reticulum|interleukin-5 receptor binding|interleukin-5 receptor complex|intracellular signaling cascade|metabolism|neurexin binding|nucleus|oxidoreductase activity|plasma membrane|protein binding|protein heterodimerization activity|protein-membrane targeting|substrate-bound cell migration, cell extension|synaptic transmission|syndecan binding miR-155 NM_000232 SGCB sarcoglycan, beta (43 kDa P + T cytoskeleton|cytoskeleton dystrophin-associated organization and biogenesis|integral glycoprotein) to plasma membrane|muscle development|sarcoglycan complex miR-155 NM_013257 SGKL serum/glucocorticoid P + T ATP binding|intracellular signaling regulated kinase-like cascade|protein amino acid phosphorylation|protein amino acid phosphorylation|protein serine/threonine kinase activity|protein serine/threonine kinase activity|protein-tyrosine kinase activity|response to stress|transferase activity miR-155 NM_005069 SIM2 single-minded homolog 2 P + T cell (Drosophila) differentiation|neurogenesis|nucleus|regulation of transcription, DNA- dependent|signal transducer activity|signal transduction|transcription|transcription factor activity miR-155 AA927480 SKI v-ski sarcoma viral P + T oncogene homolog (avian) miR-155 NM_006748 SLA Src-like-adaptor P + T SH3/SH2 adaptor activity|intracellular signaling cascade miR-155 AI684141 SMARCA4 SWI/SNF related, matrix P + T ATP binding|DNA binding|helicase associated, actin dependent activity|helicase activity|hydrolase regulator of chromatin, activity|nucleoplasm|nucleus|regulation subfamily a, member 4 of transcription from RNA polymerase II promoter|transcription|transcription coactivator activity|transcription factor activity miR-155 AB005043 SOCS1 suppressor of cytokine M + P + T JAK-STAT signaling 1 cascade|cytoplasm|insulin-like growth factor receptor binding|intracellular signaling cascade|negative regulation of JAK- STAT cascade|protein kinase binding|protein kinase inhibitor activity|regulation of cell growth|ubiquitin cycle miR-155 NM_004232 SOCS4 suppressor of cytokine M + P JAK-STAT signaling 4 cascade|cytoplasm|defense response|intracellular signaling cascade|regulation of cell growth miR-155 NM_005986 SOX1 SRY (sex determining P + T DNA binding|establishment and/or region Y)-box 1 maintenance of chromatin architecture|nucleus|regulation of transcription, DNA- dependent|regulation of transcription, DNA-dependent|transcription factor activity miR-155 AI360875 SOX11 SRY (sex determining M + T DNA region Y)-box 11 binding|neurogenesis|nucleus|regulation of transcription, DNA- dependent|transcription miR-155 AL136780 SOX6 SRY (sex determining P + T establishment and/or maintenance of region Y)-box 6 chromatin architecture|heart development|muscle development|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity miR-155 AW470841 SP3 Sp3 transcription factor P + T DNA binding|nucleus|regulation of transcription, DNA- dependent|transcription|transcriptional activator activity|transcriptional repressor activity|zinc ion binding miR-155 BF224259 SPF30 splicing factor 30, survival P + T RNA splicing|RNA splicing factor of motor neuron-related activity, transesterification mechanism|apoptosis|cytoplasm|induction of apoptosis|spliceosome assembly|spliceosome complex miR-155 NM_003120 SPI1 spleen focus forming virus M + T negative regulation of transcription (SFFV) proviral integration from RNA polymerase II oncogene spi1 promoter|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity miR-155 BE676214 SSH2 slingshot 2 P + T protein amino acid dephosphorylation|protein tyrosine/serine/threonine phosphatase activity miR-155 AF159447 SUFU suppressor of fused homolog P + T cell (Drosophila) cycle|cytoplasm|development|negative regulation of cell cycle|nucleus|proteolysis and peptidolysis|signal transducer activity|signal transduction|skeletal development|transcription corepressor activity miR-155 NM_006754 SYPL synaptophysin-like protein M + P + T integral to plasma membrane|membrane|synaptic transmission|synaptic vesicle|transport|transporter activity miR-155 NM_006286 TFDP2 transcription factor Dp-2 P + T DNA metabolism|nucleus|regulation (E2F dimerization partner 2) of cell cycle|regulation of transcription from RNA polymerase II promoter|transcription|transcription cofactor activity|transcription factor activity|transcription factor complex miR-155 AA705845 TLE4 transducin-like enhancer of P + T frizzled signaling split 4 (E(sp1) homolog, pathway|molecular_function Drosophila) unknown|nucleus|nucleus|regulation of transcription|regulation of transcription, DNA-dependent miR-155 NM_014765 TOMM20 translocase of outer P + T integral to membrane|mitochondrial mitochondrial membrane 20 outer membrane translocase (yeast) homolog complex|mitochondrion|outer membrane|protein translocase activity|protein-mitochondrial targeting miR-155 AW341649 TP53INP1 tumor protein p53 inducible P + T apoptosis|nucleus nuclear protein 1 miR-155 BC005016 TRIM2 tripartite motif-containing 2 P + T cytoplasm|myosin binding|protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-155 AA524505 TSGA zinc finger protein P + T nucleus miR-155 AW157525 TSGA14 testis specific, 14 M + P + T centrosome miR-155 X62048 WEE1 WEE1 homolog (S. pombe) P + T ATP binding|cytokinesis|mitosis|nucleus|protein amino acid phosphorylation|protein serine/threonine kinase activity|protein-tyrosine kinase activity|regulation of cell cycle|transferase activity miR-155 AC005539 WUGSC: Similar to uridine M + P + T H_NH0335J18.1 phosphorylase [Homo sapiens], mRNA sequence miR-155 NM_003413 ZIC3 Zic family member 3 P + T DNA binding|determination of heterotaxy 1 (odd-paired left/right homolog, Drosophila) symmetry|nucleus|regulation of transcription, DNA- dependent|transcription|zinc ion binding miR-155 NM_007345 ZNF236 zinc finger protein 236 P + T nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity|zinc ion binding miR-155 NM_006352 ZNF238 zinc finger protein 238 M + P + T chromosome organization and biogenesis (sensu Eukaryota)|negative regulation of transcription from RNA polymerase II promoter|nuclear chromosome|nucleic acid binding|nucleus|protein binding|protein binding|regulation of transcription, DNA- dependent|specific RNA polymerase II transcription factor activity|transcription|transcription factor activity|transport|zinc ion binding miR-21 NM_005164 ABCD2 ATP-binding cassette, sub- M + P ATP binding|ATP-binding cassette family D (ALD), member 2 (ABC) transporter complex|ATPase activity|ATPase activity, coupled to transmembrane movement of substances|fatty acid metabolism|integral to plasma membrane|membrane|peroxisome|transport miR-21 NM_001616 ACVR2 activin A receptor, type II P + T ATP binding|integral to plasma membrane|membrane|protein amino acid phosphorylation|receptor activity|transferase activity|transforming growth factor beta receptor activity|transmembrane receptor protein serine/threonine kinase signaling pathway miR-21 NM_015339 ADNP activity-dependent P + T nucleus|regulation of transcription, neuroprotector DNA-dependent|transcription factor activity|zinc ion binding miR-21 AI990366 ARHGEF7 Rho guanine nucleotide P + T guanyl-nucleotide exchange factor exchange factor (GEF) 7 activity|signal transduction miR-21 NM_017610 ARK Arkadia P + T protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-21 NM_014034 ASF1A DKFZP547E2110 protein P + T chromatin binding|loss of chromatin silencing|nucleus miR-21 NM_017680 ASPN asporin (LRR class 1) P + T miR-21 NM_000657 BCL2 B-cell CLL/lymphoma 2 P + T anti-apoptosis|endoplasmic reticulum|humoral immune response|integral to membrane|membrane|mitochondrial outer membrane|mitochondrial outer membrane|mitochondrion|negative regulation of cell proliferation|nucleus|protein binding|regulation of apoptosis|regulation of cell cycle|release of cytochrome c from mitochondria miR-21 NM_014577 BRD1 bromodomain containing 1 P + T DNA binding|cell cycle|nucleus|nucleus|regulation of transcription, DNA-dependent miR-21 AA902767 BRD2 bromodomain containing 2 P + T nucleus|protein serine/threonine kinase activity|spermatogenesis miR-21 NM_014962 BTBD3 BTB (POZ) domain P + T protein binding containing 3 miR-21 NM_006763 BTG2 BTG family, member 2 P + T DNA repair|negative regulation of cell proliferation|regulation of transcription, DNA- dependent|transcription|transcription factor activity miR-21 AK025768 C20orf99 chromosome 20 open P + T nucleic acid binding reading frame 99 miR-21 AI671238 CAPN3 Homo sapiens cDNA P + T calcium ion binding|calpain FLJ23750 fis, clone activity|calpain HEP16527, mRNA activity|intracellular|intracellular|muscle sequence development|proteolysis and peptidolysis|proteolysis and peptidolysis|signal transducer activity miR-21 NM_002981 CCL1 chemokine (C-C motif) P + T calcium ion homeostasis|cell-cell ligand 1 signaling|chemokine activity|chemotaxis|extracellular space|inflammatory response|sensory perception|signal transduction|viral life cycle miR-21 BF939071 CCM1 cerebral cavernous M + P binding|catalytic malformations 1 activity|cytoskeleton|small GTPase mediated signal transduction|small GTPase regulator activity miR-21 NM_001789 CDC25A cell division cycle 25A P + T cell proliferation|cytokinesis|hydrolase activity|intracellular|mitosis|protein amino acid dephosphorylation|protein tyrosine phosphatase activity|regulation of cyclin dependent protein kinase activity miR-21 NM_001842 CNTFR ciliary neurotrophic factor M + P + T ciliary neurotrophic factor receptor receptor activity|cytokine binding|extrinsic to membrane|neurogenesis|receptor activity|signal transduction miR-21 NM_001310 CREBL2 cAMP responsive element P + T nucleus|regulation of transcription, binding protein-like 2 DNA-dependent|signal transduction|transcription|transcription factor activity miR-21 NM_016441 CRIM1 cysteine-rich motor neuron 1 M + P + T insulin-like growth factor receptor activity|integral to membrane|membrane fraction|neurogenesis|serine-type endopeptidase inhibitor activity miR-21 NM_015396 DKFZP434A043 DKFZP434A043 protein P + T cell adhesion|cytoskeleton|mitotic chromosome condensation|protein binding|structural molecule activity miR-21 AL047650 DKFZp434A2417 endozepine-related protein P + T acyl-CoA binding precursor miR-21 AB028628 DKFZP547E2110 DKFZP547E2110 protein P + T chromatin binding|loss of chromatin silencing|nucleus miR-21 NM_031305 DKFZP564B1162 hypothetical protein P + T GTPase activator activity DKFZp564B1162 miR-21 NM_004405 DLX2 distal-less homeo box 2 P + T brain development|development|nucleus|regulation of transcription, DNA- dependent|transcription factor activity miR-21 NM_001949 E2F3 E2F transcription factor 3 M + P + T nucleus|protein binding|regulation of cell cycle|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcription factor complex|transcription initiation from RNA polymerase II promoter miR-21 NM_006795 EHD1 EH-domain containing 1 P + T ATP binding|GTP binding|GTPase activity|biological_process unknown|calcium ion binding|cellular_component unknown miR-21 NM_001412 EIF1A eukaryotic translation P + T RNA binding|eukaryotic translation initiation factor 1A initiation factor 4F complex|protein biosynthesis|translation initiation factor activity|translational initiation|translational initiation miR-21 AI832074 EIF2C2 eukaryotic translation P + T cellular_component unknown|protein initiation factor 2C, 2 biosynthesis|translation initiation factor activity miR-21 NM_006874 ELF2 E74-like factor 2 (ets P + T nucleus|nucleus|protein domain transcription factor) binding|protein binding|regulation of transcription from RNA polymerase II promoter|regulation of transcription, DNA- dependent|transcription factor activity|transcriptional activator activity|transcriptional activator activity miR-21 NM_004438 EPHA4 EphA4 P + T ATP binding|ephrin receptor activity|integral to plasma membrane|membrane|protein amino acid phosphorylation|receptor activity|signal transduction|transferase activity|transmembrane receptor protein tyrosine kinase signaling pathway miR-21 BE888593 FLJ11220 hypothetical protein P + T FLJ11220 miR-21 NM_017637 FLJ20043 hypothetical protein P + T nucleic acid binding|nucleus|zinc ion FLJ20043 binding miR-21 AF019214 HBP1 HMG-box containing M + P + T DNA binding|nucleus|regulation of protein 1 transcription, DNA-dependent miR-21 NM_000214 JAG1 jagged 1 (Alagille M + P + T Notch binding|Notch signaling syndrome) pathway|angiogenesis|calcium ion binding|calcium ion binding|cell communication|cell fate determination|development|endothelial cell differentiation|extracellular region|growth factor activity|hemopoiesis|integral to plasma membrane|keratinocyte differentiation|membrane|myoblast differentiation|neurogenesis|regulation of cell migration|regulation of cell proliferation|structural molecule activity miR-21 NM_002232 KCNA3 potassium voltage-gated M + P + T cation transport|delayed rectifier channel, shaker-related potassium channel activity|integral to subfamily, member 3 membrane|membrane|membrane fraction|potassium ion transport|voltage-gated potassium channel complex miR-21 NM_014766 KIAA0193 KIAA0193 gene product P + T cellular_component unknown|dipeptidase activity|exocytosis|proteolysis and peptidolysis miR-21 NM_014912 KIAA0940 KIAA0940 protein M + P + T nucleic acid binding miR-21 NM_014952 KIAA0945 KIAA0945 protein P + T DNA binding miR-21 NM_017780 KIAA1416 KIAA1416 protein P + T ATP binding|chromatin|chromatin assembly or disassembly|chromatin binding|helicase activity|nucleus miR-21 AB040901 KIAA1468 KIAA1468 protein P + T binding|mitotic chromosome condensation miR-21 U90268 Krit1 cerebral cavernous M + P binding|catalytic malformations 1 activity|cytoskeleton|small GTPase mediated signal transduction|small GTPase regulator activity miR-21 BF591611 LOC147632 hypothetical protein P + T oxidoreductase activity|zinc ion BC010734 binding miR-21 NM_005904 MADH7 MAD, mothers against P + T intracellular|protein binding|receptor decapentaplegic homolog 7 signaling protein serine/threonine (Drosophila) kinase signaling protein activity|regulation of transcription, DNA-dependent|response to stress|transcription|transforming growth factor beta receptor signaling pathway|transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity miR-21 NM_025146 MAK3P likely ortholog of mouse P + T N-acetyltransferase activity Mak3p homolog (S. cerevisiae) miR-21 NM_014319 MAN1 integral inner nuclear P + T integral to membrane|integral to membrane protein nuclear inner membrane|membrane fraction|nuclear membrane|nucleotide binding miR-21 AW025150 MAP3K12 mitogen-activated protein M + T ATP binding|JNK kinase kinase kinase 12 cascade|cytoplasm|magnesium ion binding|plasma membrane|protein amino acid phosphorylation|protein kinase cascade|protein serine/threonine kinase activity|protein-tyrosine kinase activity|transferase activity miR-21 NM_012325 MAPRE1 microtubule-associated P + T cell protein, RP/EB family, proliferation|cytokinesis|microtubule member 1 binding|mitosis|protein C-terminus binding|regulation of cell cycle miR-21 NM_002380 MATN2 matrilin 2 P + T biological_process unknown|calcium ion binding|extracellular matrix (sensu Metazoa) miR-21 NM_018834 MATR3 matrin 3 M + P + T RNA binding|nuclear inner membrane|nucleotide binding|nucleus|structural molecule activity|zinc ion binding miR-21 NM_021038 MBNL1 muscleblind-like M + P + T cytoplasm|double-stranded RNA (Drosophila) binding|embryonic development (sensu Mammalia)|embryonic limb morphogenesis|muscle development|myoblast differentiation|neurogenesis|nucleic acid binding|nucleus|nucleus miR-21 AI139252 MGC16063 ribosomal protein L35a P + T JAK-STAT cascade|acute-phase response|calcium ion binding|cell motility|cytoplasm|hematopoietin/interferon- class (D200-domain) cytokine receptor signal transducer activity|intracellular signaling cascade|negative regulation of transcription from RNA polymerase II promoter|neurogenesis|nucleus|nu- cleus|regulation of transcription, DNA- dependent|signal transducer activity|transcription|transcription factor activity|transcription factor activity miR-21 BC004162 MGC2452 hypothetical protein P + T fatty acid metabolism|generation of MGC2452 precursor metabolites and energy|ligand-dependent nuclear receptor activity|lipid metabolism|nucleus|nucleus|regulation of transcription, DNA- dependent|steroid hormone receptor activity|transcription|transcription factor activity|transcription factor activity|transcription from RNA polymerase II promoter miR-21 NM_024052 MGC3048 hypothetical protein P + T MGC3048 miR-21 AB049636 MRPL9 mitochondrial ribosomal P + T mitochondrion|protein protein L9 biosynthesis|ribosome|structural constituent of ribosome miR-21 NM_015678 NBEA neurobeachin P + T Golgi trans face|cytosol|endomembrane system|plasma membrane|post-Golgi transport|postsynaptic membrane|protein kinase A binding miR-21 AI700518 NFIB nuclear factor I/B M + T DNA replication|nucleus|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity|transcription factor activity miR-21 NM_002527 NTF3 neurotrophin 3 M + P anti-apoptosis|cell motility|cell-cell signaling|growth factor activity|neurogenesis|signal transduction miR-21 U24223 PCBP1 poly(rC) binding protein 1 M + P + T RNA binding|catalytic activity|cytoplasm|mRNA metabolism|nucleus|ribonucleoprotein complex|single-stranded DNA binding miR-21 NM_005016 PCBP2 poly(rC) binding protein 2 M + T DNA binding|RNA binding|cytoplasm|mRNA metabolism|nucleic acid binding|nucleus|ribonucleoprotein complex miR-21 NM_014456 PDCD4 programmed cell death 4 P + T apoptosis (neoplastic transformation inhibitor) miR-21 AF338650 PDZD2 PDZ domain containing 2 P + T miR-21 NM_000325 PITX2 paired-like homeodomain M + P + T determination of left/right transcription factor 2 symmetry|development|nucleus|organo- genesis|regulation of transcription, DNA-dependent|transcription factor activity miR-21 NM_002655 PLAG1 pleiomorphic adenoma gene 1 P + T nucleic acid binding|nucleus|transcription factor activity|zinc ion binding miR-21 NM_005036 PPARA peroxisome proliferative P + T fatty acid metabolism|generation of activated receptor, alpha precursor metabolites and energy|ligand-dependent nuclear receptor activity|lipid metabolism|nucleus|nucleus|regulation of transcription, DNA- dependent|steroid hormone receptor activity|transcription|transcription factor activity|transcription factor activity|transcription from RNA polymerase II promoter miR-21 NM_002711 PPP1R3A protein phosphatase 1, P + T carbohydrate metabolism|glycogen regulatory (inhibitor) metabolism|hydrolase subunit 3A (glycogen and activity|integral to sarcoplasmic reticulum membrane|phosphoprotein binding subunit, skeletal phosphatase activity|type 1 muscle) serine/threonine specific protein phosphatase inhibitor activity miR-21 NM_000944 PPP3CA protein phosphatase 3 P + T calcineurin complex|calcium ion (formerly 2B), catalytic binding|calmodulin subunit, alpha isoform binding|hydrolase activity|protein (calcineurin A alpha) amino acid dephosphorylation|protein serine/threonine phosphatase activity miR-21 NM_018569 PRO0971 hypothetical protein P + T PRO0971 miR-21 AA156948 PRPF4B PRP4 pre-mRNA processing M + T ATP binding|RNA splicing|nuclear factor 4 homolog B (yeast) mRNA splicing, via spliceosome|nucleus|protein amino acid phosphorylation|protein serine/threonine kinase activity|transferase activity miR-21 BF337790 PURB purine-rich element binding M + P + T protein B miR-21 NM_002869 RAB6A RAB6A, member RAS P + T GTP binding|GTPase activity|Golgi oncogene family apparatus|protein transport|small GTPase mediated signal transduction miR-21 AL136727 RAB6C RAB6C, member RAS P + T GTP binding|GTPase oncogene family activity|intracellular|protein transport|response to drug|small GTPase mediated signal transduction miR-21 NM_002890 RASA1 RAS p21 protein activator P + T Ras GTPase activator (GTPase activating protein) 1 activity|intracellular signaling cascade miR-21 NM_005739 RASGRP1 RAS guanyl releasing P + T Ras guanyl-nucleotide exchange protein 1 (calcium and factor activity|Ras protein signal DAG-regulated) transduction|calcium ion binding|calcium ion binding|diacylglycerol binding|guanyl-nucleotide exchange factor activity|membrane fraction|small GTPase mediated signal transduction miR-21 NM_021111 RECK reversion-inducing-cysteine- M + P + T cell cycle|membrane|membrane rich protein with kazal fraction|metalloendopeptidase motifs inhibitor activity|negative regulation of cell cycle|serine-type endopeptidase inhibitor activity miR-21 NM_006915 RP2 retinitis pigmentosa 2 (X- P + T beta-tubulin linked recessive) folding|membrane|sensory perception|unfolded protein binding|visual perception miR-21 AA906056 RPS6KA3 ribosomal protein S6 kinase, M + T ATP binding|central nervous system 90 kDa, polypeptide 3 development|protein amino acid phosphorylation|protein serine/threonine kinase activity|signal transduction|skeletal development|transferase activity miR-21 NM_002971 SATB1 special AT-rich sequence M + P + T double-stranded DNA binding protein 1 (binds to binding|establishment and/or nuclear matrix/scaffold- maintenance of chromatin associating DNA's) architecture|nucleus|regulation of transcription, DNA- dependent|transcription factor activity miR-21 NM_014191 SCN8A sodium channel, voltage M + P + T ATP binding|cation channel gated, type VIII, alpha activity|cation transport|integral to polypeptide membrane|membrane|neurogenesis|sodium ion transport|voltage-gated sodium channel activity|voltage- gated sodium channel complex miR-21 AA927480 SKI v-ski sarcoma viral M + P + T oncogene homolog (avian) miR-21 NM_003983 SLC7A6 solute carrier family 7 P + T amino acid metabolism|amino acid (cationic amino acid transport|amino acid-polyamine transporter, y + system), transporter activity|integral to plasma member 6 membrane|plasma membrane|protein complex assembly|transport miR-21 NM_006359 SLC9A6 solute carrier family 9 P + T antiporter activity|endoplasmic (sodium/hydrogen reticulum membrane|integral to exchanger), isoform 6 membrane|integral to membrane|ion transport|microsome|mitochondrion|regulation of pH|sodium ion transport|sodium:hydrogen antiporter activity|solute:hydrogen antiporter activity miR-21 NM_003076 SMARCD1 SWI/SNF related, matrix P + T chromatin remodeling|chromatin associated, actin dependent remodeling complex|regulation of regulator of chromatin, transcription from RNA polymerase subfamily d, member 1 II promoter|transcription coactivator activity miR-21 AI669815 SOX2 SRY (sex determining P + T establishment and/or maintenance of region Y)-box 2 chromatin architecture|nucleus|regulation of transcription, DNA- dependent|transcription|transcription factor activity miR-21 NM_006940 SOX5 SRY (sex determining P + T nucleus|regulation of transcription, region Y)-box 5 DNA- dependent|transcription|transcription factor activity|transcription from RNA polymerase II promoter miR-21 AI808807 SOX7 SRY (sex determining P + T DNA binding|nucleus|regulation of region Y)-box 7 transcription, DNA- dependent|transcription miR-21 NM_006717 SPIN Spindling P + T gametogenesis|ribonucleoprotein complex miR-21 NM_005842 SPRY2 sprouty homolog 2 P + T cell-cell (Drosophila) signaling|development|mem- brane|organogenesis|regulation of signal transduction miR-21 NM_006751 SSFA2 sperm specific antigen 2 P + T plasma membrane miR-21 NM_006603 STAG2 stromal antigen 2 P + T cell cycle|chromosome segregation|cytokinesis|meiosis|mito- sis|molecular_function unknown|nucleus miR-21 BC000627 STAT3 signal transducer and P + T JAK-STAT cascade|acute-phase activator of transcription 3 response|calcium ion binding|cell (acute-phase response motility|cytoplasm|hematopoietin|interferon- factor) class (D200-domain) cytokine receptor signal transducer activity|intracellular signaling cascade|negative regulation of transcription from RNA polymerase II promoter|neurogenesis|nucleus|nu- cleus|regulation of transcription, DNA- dependent|signal transducer activity|transcription|transcription factor activity|transcription factor activity miR-21 AW138827 TAF5 TAF5 RNA polymerase II, P + T nucleus|regulation of transcription, TATA box binding protein DNA-dependent|transcription factor (TBP)-associated factor, TFIID complex|transcription factor 100 kDa activity miR-21 BF591040 TAGAP T-cell activation GTPase P + T GTPase activator activity activating protein miR-21 NM_000358 TGFBI transforming growth factor, M + P + T cell adhesion|cell beta-induced, 68 kDa proliferation|extracellular matrix (sensu Metazoa)|extracellular space|integrin binding|negative regulation of cell adhesion|protein binding|sensory perception|visual perception miR-21 NM_000362 TIMP3 tissue inhibitor of P + T enzyme inhibitor metalloproteinase 3 (Sorsby activity|extracellular matrix (sensu fundus dystrophy, Metazoa)|extracellular matrix (sensu pseudoinflammatory) Metazoa)|induction of apoptosis by extracellular signals|metalloendopeptidase inhibitor activity|sensory perception|visual perception miR-21 AA149745 TRIM2 tripartite motif-containing 2 M + P + T cytoplasm|myosin binding|protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-21 AF346629 TRPM7 transient receptor potential P + T ATP binding|calcium channel cation channel, subfamily activity|calcium ion transport|cation M, member 7 transport|integral to membrane|membrane|protein amino acid phosphorylation|protein serine/threonine kinase activity|transferase activity miR-21 AI745185 YAP1 Yes-associated protein 1, P + T 65 kDa miR-21 NM_005667 ZFP103 zinc finger protein 103 P + T central nervous system homolog (mouse) development|integral to membrane|protein ubiquitination|ubiquitin ligase complex|ubiquitin-protein ligase activity|zinc ion binding miR-21 N62196 ZNF367 zinc finger protein 367 M + P + T nucleic acid binding|nucleus|zinc ion binding M = MiRanda P = PicTar T = TargetScan

Example 3 Bio-Pathological Features and microRNA Expression

Materials and Methods

Immunohistochemical Analysis of Breast Cancer Samples.

Staining procedures were performed as described (Querzoli, P., et al., Anal. Quant. Cytol. Histol. 21:151-160 (1999)). Hormonal receptors were evaluated with 6F11 antibody for estrogen receptor α (ER) and PGR-1A6 antibody for progesterone receptor (PR) (Ventana, Tucson, Ariz., U.S.A.). The proliferation index was assessed with MIB1 antibody (DAKO, Copenhagen). ERBB2 was detected with CB11 antibody (Ventana, Tucson, Ariz., U.S.A.) and p53 protein expression was examined with DO7 antibody (Ventana, Tucson, Ariz., U.S.A.). Only tumor cells with distinct nuclear immunostaining for ER, PR, Mib1 and p53 were recorded as positive. Tumor cells were considered positive for ERBB2 when they showed distinct membrane immunoreactivity.

To perform a quantitative analysis of the expression of these various biological markers, the Eureka Menarini computerized image analysis system was used. For each tumor section, at least 20 microscopic fields of invasive carcinoma were measured using a 40× objective. The following cut-off values were employed: 10% of positive nuclear area for ER, PR, c-erbB2 and p53, 13% of nuclei expressing Mib1 was introduced to discriminate cases with high and low proliferative activity.

Results

To evaluate whether a correlation exists between various bio-pathological features associated with breast cancer and the expression of particular miRNAs, we generated and compared miRNA expression profiles for various cancer samples associated with the presence or absence of a particular breast cancer feature. In particular, we analyzed breast cancers with lobular or ductal histotypes, breast cancers with differential expression of either estrogen receptor alpha (ER) or progesterone receptor, and breast cancers with differences in lymph node metastasis, vascular invasion, proliferation index, and expression of ERBB2 and p53.

Expression profiles of lobular or ductal and +/−ERBB2 expression classes did not reveal any microRNAs that were differentially-expressed, while all other comparisons revealed a small number of differentially-expressed microRNAs (P<0.05). The results of this analysis are shown in FIG. 4.

Differentially-expressed miRNA families were identified for various bio-pathological features that are associated with human breast cancer. For example, all miR-30 miRNAs are down-regulated in both ER− and PR− tumors, suggesting that expression of miR-30 miRNAs is regulated by these hormones. In addition, the expression of various let-7 miRNAs was down-regulated in breast cancer samples with either lymph node metastasis or a high proliferation index, suggesting that reduced let-7 expression could be associated with a poor prognosis, a result that is consistent with previous findings. The discovery that the let-7 family of miRNAs regulates the expression of members of the RAS oncogene family provides a potential explanation for the role of let-7 miRNAs in human cancer.

miR-145 and miR-21, two miRNAs whose expression could differentiate cancer or normal tissues, were also differentially-expressed in cancers with a different proliferation index or different tumor stage. In particular, miR-145 is progressively down-regulated from normal breast to cancers with a high proliferation index. Similarly, miR-21 is progressively up-regulated from normal breast to cancers with high tumor stage. These findings suggest that deregulation of these two miRNAs may affect critical molecular events involved in tumor progression.

Another miRNA potentially involved in cancer progression is miR-9-3. miR-9-3 was downregulated in breast cancers with either high vascular invasion or lymph node metastasis, suggesting that its down-regulation was acquired during the course of tumor progression and, in particular, during the acquisition of metastatic potential.

The relevant teachings of all publications cited herein that have not explicitly been incorporated by reference, are incorporated herein by reference in their entirety. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

1. A pharmaceutical composition for treating breast cancer, comprising at least one isolated miR gene product, and a pharmaceutically-acceptable carrier;

wherein the at least one isolated miR gene product is selected from the group consisting of: miR-145, miR-10b, miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, miR-101-1, miR-143 and combinations thereof.

2. A pharmaceutical composition for treating breast cancer, comprising at least one miR expression inhibitor compound, and a pharmaceutically-acceptable carrier:

wherein the at least one miR inhibitor compound is selected from the group consisting of miR-21, miR-155, miR-009-1 (miR-131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-213, let-7i (let-7d-v2), miR-122a, miR-128b, miR-136, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210, miR-213 and combinations thereof.

3. A pharmaceutical composition for treating breast cancer, comprising at least one isolated miR gene product, wherein the breast cancer is associated with one or more prognostic markers and the at least one miR gene product are selected from the group consisting of:

(i) the breast cancer is a breast cancer associated with estrogen receptor expression and the miR gene product is selected from the group consisting of miR-26a, miR-26b, miR-102 (miR-29b), miR-30a-5p, miR-30b, miR-30c, miR-30d, miR-185, miR-191, miR-206, miR-212, and combinations thereof;
(ii) the breast cancer is a breast cancer associated with progesterone receptor expression and the miR gene product is selected from the group consisting of let-7c, miR-26a, miR-29b, miR-30a-5p, miR-30b, miR-30c, miR-30d, and combinations thereof;
(iii) the breast cancer is a breast cancer associated with positive lymph node metastasis and the miR gene product is selected from the group consisting of let-7f-1, let-7a-3, let-7a-2, miR-9-3, and combinations thereof;
(iv) the breast cancer is a breast cancer associated with a high proliferative index and the miR gene product is selected from the group consisting of let-7c, let-7d, miR-26a, miR-26b, miR-30a-5p, miR-102, miR-145, and combinations thereof;
(v) the breast cancer is a breast cancer associated with detectable p53 expression and the miR gene product is selected from the group consisting of miR-16a, miR-128b and a combination thereof;
(vi) the breast cancer is a breast cancer associated with high vascular invasion and the miR gene product is selected from the group consisting of miR-9-3, miR-10b, miR-27a, miR-29a, miR-123, miR-205 and combinations thereof; and
(vii) the breast cancer is a breast cancer associated with an advanced tumor stage and the miR gene product is selected from the group consisting of miR-9-2, miR-15-a, miR-21, miR-30a-s, miR-133a-1, miR-137, miR-153-2, miR-154, miR-181a, miR-203, miR-213, and combinations thereof.
Patent History
Publication number: 20160251659
Type: Application
Filed: May 16, 2016
Publication Date: Sep 1, 2016
Applicant: The Ohio State University Research Foundation (Columbus, OH)
Inventors: Carlo M. Croce (Columbus, OH), George A. Calin (Pearland, TX)
Application Number: 15/155,479
Classifications
International Classification: C12N 15/113 (20060101);