Abstract
microRNAs (miRNAs) are evolutionarily conserved small noncoding RNAs, also known as micromanagers of gene expression. Polymorphisms in the miRNA pathway (miR-polymorphisms) are emerging as powerful tools to study the biology of a disease and have the potential to be used in disease prognosis and diagnosis. Advancements in the miRNA field also indicate a clear involvement of deregulated miRNA gene signatures in cancers, and several polymorphisms in pre-miRNA, miRNA binding sites or targets have been found to be associated with various cancers. The miRNA polymorphisms have also been reported to influence tumor aggressiveness as well as survival of cancer patients. miRNAs have a revolutionary impact on cancer research over recent years. They emerge as important players in tumorigenesis, leading to a paradigm shift in oncology. The extensive and comprehensive use of miRNA microarrays has enabled the identification of a number of miRNAs as potential biomarkers for cancer. Many miRNAs have been identified to act as oncogenes, tumor suppressors, or even modulators of cancer stem cells and metastasis. Some studies not only reported the identified miRNA biomarkers, but also deciphered their target genes and the underlying mechanisms. The rapid discovery of many miRNA targets and their relevant pathways has contributed to the development of miRNA-based therapeutics.
Key Words: Micro RNA, Cancer, Polymorphism, Epigenetic, Biomarker
Full Text
The Full Text of this article is available as a PDF (162.6 KB).
References
- 1.Krek A., Grun D., Poy M.N., Wolf R., Rosenberg L., Epstein E.J., et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37:495–500. doi: 10.1038/ng1536. [DOI] [PubMed] [Google Scholar]
- 2.Berezikov E., Guryev V., Belt J., Wienholds E., Plasterk R.H., Cuppen E. Phylogenetic shadowing and computational identification of human microRNA genes. Cell. 2005;120:21–24. doi: 10.1016/j.cell.2004.12.031. [DOI] [PubMed] [Google Scholar]
- 3.Winter J., Jung S., Keller S., Gregory R.I., Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11:228–234. doi: 10.1038/ncb0309-228. [DOI] [PubMed] [Google Scholar]
- 4.Zeng Y. Principles of micro-RNA production and maturation. Oncogene. 2006;25:6156–6162. doi: 10.1038/sj.onc.1209908. [DOI] [PubMed] [Google Scholar]
- 5.Baek D., Villen J., Shin C., Camargo F.D., Gygi S.P., Bartel D.P. The impact of microRNAs on protein output. Nature. 2008;455:64–71. doi: 10.1038/nature07242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Zhao Y., Srivastava D. A developmental view of microRNA function. Trends Biochem Sci. 2007;32:189–197. doi: 10.1016/j.tibs.2007.02.006. [DOI] [PubMed] [Google Scholar]
- 7.Kertesz M., Iovino N., Unnerstall U., Gaul U., Segal E. The role of site accessibility in microRNA target recognition. Nat Genet. 2007;39:1278–1284. doi: 10.1038/ng2135. [DOI] [PubMed] [Google Scholar]
- 8.Chen K., Song F., Calin G.A., Wei Q., Hao X., Zhang W. Polymorphisms in microRNA targets: a gold mine for molecular epidemiology. Carcinogenesis. 2008;29:1306–1311. doi: 10.1093/carcin/bgn116. [DOI] [PubMed] [Google Scholar]
- 9.Borel C., Antonarakis S.E. Functional genetic variation of human miRNAs and phenotypic consequences. Mamm Genome. 2008;19:503–509. doi: 10.1007/s00335-008-9137-6. [DOI] [PubMed] [Google Scholar]
- 10.Mishra P.J., Humeniuk R., Longo-Sorbello G.S., Banerjee D., Bertino J.R. A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci USA. 2007;104:13513–13518. doi: 10.1073/pnas.0706217104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Tan Z., Randall G., Fan J., Camoretti-Mercado B., Brockman-Schneider R., Pan L., et al. Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Hum Genet. 2007;81:829–834. doi: 10.1086/521200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Zhang B., Pan X., Cobb G.P., Anderson T.A. MicroRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12. doi: 10.1016/j.ydbio.2006.08.028. [DOI] [PubMed] [Google Scholar]
- 13.Zhu S., Wu H., Wu F., Nie D., Sheng S., Mo Y.Y. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008;18:350–359. doi: 10.1038/cr.2008.24. [DOI] [PubMed] [Google Scholar]
- 14.Duan R., Pak C., Jin P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet. 2007;16:1124–1131. doi: 10.1093/hmg/ddm062. [DOI] [PubMed] [Google Scholar]
- 15.Landi D., Gemignani F., Barale R., Landi S. A catalog of polymorphisms falling in microRNA-binding regions of cancer genes. DNA Cell Biol. 2008;27:35–43. doi: 10.1089/dna.2007.0650. [DOI] [PubMed] [Google Scholar]
- 16.Raveche E.S., Salerno E., Scaglione B.J., Manohar V., Abbasi F., Lin Y.C., et al. Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood. 2007;109:5079–5086. doi: 10.1182/blood-2007-02-071225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Calin G.A., Liu C.G., Sevignani C., Ferracin M., Felli N., Dumitru C.D., et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci USA. 2004;101:11755–11760. doi: 10.1073/pnas.0404432101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Hu Z., Chen J., Tian T., Zhou X., Gu H., Xu L., et al. Genetic variants of miRNA sequences and non-small cell lung cancer survival. J Clin Invest. 2008;118:2600–2608. doi: 10.1172/JCI32053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Hu Z., Liang J., Wang Z., Tian T., Zhou X., Chen J., et al. Common genetic variants in pre-microRNAs were associated with increased risk of breast cancer in Chinese women. Hum Mutat. 2009;30:79–84. doi: 10.1002/humu.20837. [DOI] [PubMed] [Google Scholar]
- 20.Jazdzewski K., Murray E.L., Franssila K., Jarzab B., Schoenberg D.R., Chapelle A. Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci USA. 2008;105:7269–7274. doi: 10.1073/pnas.0802682105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Warthmann N., Das S., Lanz C., Weigel D. Comparative analysis of the MIR319a microRNA locus in Arabidopsis and related Brassicaceae. Mol Biol Evol. 2008;25:892–902. doi: 10.1093/molbev/msn029. [DOI] [PubMed] [Google Scholar]
- 22.Didiano D., Hobert O. Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions. Nat Struct Mol Biol. 2006;13:849–851. doi: 10.1038/nsmb1138. [DOI] [PubMed] [Google Scholar]
- 23.Saunders M.A., Liang H., Li W.H. Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci U S A. 2007;104:3300–3305. doi: 10.1073/pnas.0611347104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Evans SC, Kourtidis A, Markham TS, Miller J, Conklin DS, Torres AS. MicroRNA Target Detection and Analysis for Genes Related to Breast Cancer Using MDLcompress. EURASIP J Bioinform Syst Biol 2007;43670. [DOI] [PMC free article] [PubMed]
- 25.Gottwein E., Cai X., Cullen B.R. A novel assay for viral microRNA function identifies a single nucleotide polymorphism that affects Drosha processing. J Virol. 2006;80:5321–5326. doi: 10.1128/JVI.02734-05. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Zhang R., Su B. MicroRNA regulation and the variability of human cortical gene expression. Nucleic Acids Res. 2008;36:4621–4628. doi: 10.1093/nar/gkn431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Zhao Y., Samal E., Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature. 2005;436:214–220. doi: 10.1038/nature03817. [DOI] [PubMed] [Google Scholar]
- 28.Jing Q., Huang S., Guth S., Zarubin T., Motoyama A., Chen J., et al. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell. 2005;120:623–634. doi: 10.1016/j.cell.2004.12.038. [DOI] [PubMed] [Google Scholar]
- 29.Hon L.S., Zhang Z. The roles of binding site arrangement and combinatorial targeting in microRNA repression of gene expression. Genome Biol. 2007;8:R166. doi: 10.1186/gb-2007-8-8-r166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Lehmann U., Hasemeier B., Christgen M., Muller M., Romermann D., Langer F., et al. Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer. J Pathol. 2008;214:17–24. doi: 10.1002/path.2251. [DOI] [PubMed] [Google Scholar]
- 31.Calin G.A., Dumitru C.D., Shimizu M., Bichi R., Zupo S., Noch E., et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99:15524–15529. doi: 10.1073/pnas.242606799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Iorio M.V., Ferracin M., Liu C.G., Veronese A., Spizzo R., Sabbioni S., et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65:7065–7070. doi: 10.1158/0008-5472.CAN-05-1783. [DOI] [PubMed] [Google Scholar]
- 33.Cheng A.M., Byrom M.W., Shelton J., Ford L.P. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 2005;33:1290–1297. doi: 10.1093/nar/gki200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Ruan K., Fang X., Ouyang G. MicroRNAs: Novel regulators in the hallmarks of human cancer. Cancer Letters. 2009;285:116–126. doi: 10.1016/j.canlet.2009.04.031. [DOI] [PubMed] [Google Scholar]
- 35.Zhang B.H., Pan X.P., Cobb G.P., Anderson T.A. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12. doi: 10.1016/j.ydbio.2006.08.028. [DOI] [PubMed] [Google Scholar]
- 36.He L., Thomson J.M., Hemann M.T., Hernando-Monge E., Mu D., Goodson S., et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–833. doi: 10.1038/nature03552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.He L., He X., Lim L.P., Stanchina E., Xuan Z., Liang Y., et al. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447:1130–1134. doi: 10.1038/nature05939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Croce C.M. Oncogenes and cancer. N Engl J Med. 2008;358:502–511. doi: 10.1056/NEJMra072367. [DOI] [PubMed] [Google Scholar]
- 39.Calin G.A., Croce C.M. MicroRNA signatures in human cancers. Nature Rev Cancer. 2006;6:857–866. doi: 10.1038/nrc1997. [DOI] [PubMed] [Google Scholar]
- 40.Yanaihara N., Caplen N., Bowman E., Seike M., Kumamoto K., Yi M., et al. Unique microRNA molecular profiles in lungcancer diagnosis and prognosis. Cancer Cell. 2006;9:189–198. doi: 10.1016/j.ccr.2006.01.025. [DOI] [PubMed] [Google Scholar]
- 41.Volinia S., Calin G.A., Liu C.G., Ambs S., Cimmino A., Petrocca F., et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–2261. doi: 10.1073/pnas.0510565103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Hanahan D., Weinberg R.A. The hallmarks of cancer. Cell. 2000;100:57–70. doi: 10.1016/S0092-8674(00)81683-9. [DOI] [PubMed] [Google Scholar]
- 43.Ye Y., Wang K.K., Gu J., Yang H., Lin J., Ajani J.A., et al. Genetic Variations in MicroRNA-Related Genes Are Novel Susceptibility Loci for Esophageal Cancer Risk. Cancer Prev Res. 2008;1:460–469. doi: 10.1158/1940-6207.CAPR-08-0135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Brendle A., Lei H., Brandt A., Johansson R., Enquist K., Henriksson R., et al. Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer: ITGB4 as prognostic marker. Carcinogenesis. 2008;29:1394–1399. doi: 10.1093/carcin/bgn126. [DOI] [PubMed] [Google Scholar]
- 45.Manolio T.A., Brooks L.D., Collins F.S. A HapMap harvest of insights into the genetics of common disease. J Clin Invest. 2008;118:1590–1605. doi: 10.1172/JCI34772. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Mayr C., Hemann M.T., Bartel D.P. Disrupting the Pairing Between let-7 and Hmga2 Enhances Oncogenic Transformation. Science. 2007;315:1576–1579. doi: 10.1126/science.1137999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Yang H., Dinney C.P., Ye Y., Zhu Y., Grossman H.B., Wu X. Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer. Cancer Res. 2008;68:2530–2537. doi: 10.1158/0008-5472.CAN-07-5991. [DOI] [PubMed] [Google Scholar]
- 48.Cowland J.B., Hother C., Gronbaek K. MicroRNAs and cancer. APMIS. 2007;115:1090–1106. doi: 10.1111/j.1600-0463.2007.apm_775.xml.x. [DOI] [PubMed] [Google Scholar]
- 49.Lu J., Getz G., Miska E.A., varez-Saavedra E., Lamb J., Peck D., et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–838. doi: 10.1038/nature03702. [DOI] [PubMed] [Google Scholar]
- 50.Lawrie H. microRNA expression in lymphoid malignancies: new hope for diagnosis and therapy? J Cell Mol Med. 2008;12(5A):1432–1444. doi: 10.1111/j.1582-4934.2008.00399.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Chen C.Z. MicroRNAs as oncogenes and tumor suppressors. N Engl J Med. 2005;353:1768–1771. doi: 10.1056/NEJMp058190. [DOI] [PubMed] [Google Scholar]
- 52.Drakaki A., Iliopoulos D. MicroRNA Gene Networks in Oncogenesis. Current Genomics. 2009;10:35–41. doi: 10.2174/138920209787581299. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Sethupathy P., Collins F.S. MicroRNA target site polymorphisms and human disease. Trends Genet. 2008;24:489–497. doi: 10.1016/j.tig.2008.07.004. [DOI] [PubMed] [Google Scholar]
- 54.Glinsky G.V. An SNP-guided microRNA map of fifteen common human disorders identifies a consensus disease phenocode aiming at principal components of the nuclear import pathway. Cell Cycle. 2008;7:2570–2583. doi: 10.4161/cc.7.16.6524. [DOI] [PubMed] [Google Scholar]
- 55.Marcucci G., Maharry K., Radmacher M.D., Mrozek K., Vukosavljevic T., Paschka P., et al. Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study. J Clin Oncol. 2008;26:5078–5087. doi: 10.1200/JCO.2008.17.5554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Shi X.-B., Tepper C.G., deVere White R.W. microRNAs and prostate cancer. J Cell Mol Med. 2008;12(5A):1456–1465. doi: 10.1111/j.1582-4934.2008.00420.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Ozen M., Creighton C.J., Ozdemir M., Ittmann M. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008;27:1788–1793. doi: 10.1038/sj.onc.1210809. [DOI] [PubMed] [Google Scholar]
- 58.Porkka K.P., Pfeiffer M.J., Waltering K.K., Vessella R.L., Tammela T.L., Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007;67:6130. doi: 10.1158/0008-5472.CAN-07-0533. [DOI] [PubMed] [Google Scholar]
- 59.Lynam-Lennon N., Maher S.G., Reynolds J.V. The roles of microRNA in cancer and apoptosis. Biol Rev. 2009;84:55–71. doi: 10.1111/j.1469-185X.2008.00061.x. [DOI] [PubMed] [Google Scholar]
- 60.Weidhaas J.B., Babar I., Nallur S.M., Trang P., Roush S., Boehm M., et al. MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res. 2007;67:11111–11116. doi: 10.1158/0008-5472.CAN-07-2858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Weidhaas J.B., Eisenmann D.M., Holub J.M., Nallur S.V. A conserved RAS/mitogen-activated protein kinase pathway regulates DNA damage-induced cell death postirradiation in Radelegans. Cancer Res. 2006;66:10434–10438. doi: 10.1158/0008-5472.CAN-06-2182. [DOI] [PubMed] [Google Scholar]
- 62.Josson S., Sung S.Y., Lao K., Chung L.W., Johnstone P.A. Radiation modulation of MicroRNA in prostate cancer cell lines. Prostate. 2008;68:1599–1606. doi: 10.1002/pros.20827. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Esquela-Kerscher A., Slack F.J. Oncomirs — microRNAs with a role in cancer. Nature Rev Cancer. 2006;6:259–269. doi: 10.1038/nrc1840. [DOI] [PubMed] [Google Scholar]
- 64.Wiemer E.A.C. The role of microRNAs in cancer: No small matter. Eur J Cancer. 2007;43:1529–1544. doi: 10.1016/j.ejca.2007.04.002. [DOI] [PubMed] [Google Scholar]
- 65.Ma L., Teruya-Feldstein J., Weinberg R.A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007;449:682–688. doi: 10.1038/nature06174. [DOI] [PubMed] [Google Scholar]
- 66.Zhang B., Farwell M.A. microRNAs: a new emerging class of players for disease diagnostics and gene therapy. J Cell Mol Med. 2008;12(1):3–21. doi: 10.1111/j.1582-4934.2007.00196.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Ivan M., Harris A.L., Martelli F., Kulshreshtha R. Hypoxia response and microRNAs: no longer two separate worlds. J Cell Mol Med. 2008;12:1426–1431. doi: 10.1111/j.1582-4934.2008.00398.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Kulshreshtha R., Ferracin M., Wojcik S.E., Garzon R., Alder H., Agosto-Perez F.J., et al. A microRNA signature of hypoxia. Mol Cell Biol. 2007;27:1859–1867. doi: 10.1128/MCB.01395-06. [DOI] [PMC free article] [PubMed] [Google Scholar]