MicroRNAs and Their Role in Cancer

Abstract

Microribonucleic acids (miRNAs) are short, noncoding RNAs that act as post‐transcription regulators and are able to modulate the expression of hundreds of target genes. In the past few years, they gained a very important role in oncology. Indeed, many of them can be now considered tumour suppressor genes or oncogenes. In cancer, they appeared to have a dysregulated expression due to genetic aberrations, altered methylation or irregular processing that finally lead to an altered modulation of their target genes.

Each cancer type displayed specific alterations of specific miRNAs, and their exceptional stability confer to miRNAs a strong potential as cancer therapeutics. Finally, miRNAs are stable and detectable as circulating molecules in blood of cancer patients. For this reason they are going to become useful biomarkers in cancer diagnostics.

Key Concepts:

  • In the last few years, miRNAs have produced a micro‐revolution in cancer research because of their action as oncogenes or tumour suppressor genes.

  • miRNA expression profiling may be used for cancer classification and for the identification of cancer subtypes.

  • A promising role of miRNA in prognosis stratification has been proposed.

  • Several studies indicated miRNAs as predictors of drug response.

  • miRNA polymorphisms may modify innate genetic susceptibility to cancer: SNPs in miRNAs and their gene targets may alter cancer susceptibility.

  • miRNAs as cancer biomarkers detected in plasma or serum of patients seem to be very promising in terms of efficacy and specificity.

  • miRNA may represent important therapeutic targets and can be effectively targeted in vivo.

Keywords: microRNA; cancer; oncogene; tumour suppressor gene; therapy; prognosis; biomarker

Figure 1.

(a) Tumour suppressor microRNAs. Mechanisms that reduce miRNA expression in cancer cells finally lead to reduced levels of miRNAs in cytoplasm and impair their action on target genes through 3′‐UTR binding. Oncogenic proteins that are regulated by these miRNAs are therefore translated at higher levels than in normal cells. (b) Oncogenic microRNAs. An increased production of microRNAs in cancer cells determines a more powerful inhibition of target genes. If the target is a tumour suppressor gene, its expression is reduced and the protein cannot exert its protective action.

Figure 2.

Targets of microRNAs in cancer cells. Deregulation of miRNAs in cancer cells may occur by genetic or epigenetic changes, by anomalous transcription factors expression and by abnormal responsiveness to various stimuli. Increased or impaired miRNA expression may ultimately affect the expression of target genes. As a result, cells may not differentiate or undergo apoptosis, or they may increase their proliferation rate, motility and invasiveness, properties that represent hallmarks of cancer.

close

References

Bloomston M, Frankel WL, Petrocca F et al. (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. Journal of the American Medical Association 297: 1901–1908.

Boyerinas B, Park SM, Shomron N et al. (2008) Identification of let‐7‐regulated oncofetal genes. Cancer Research 68: 2587–2591.

Budhu A, Jia HL, Forgues M et al. (2008) Identification of metastasis‐related microRNAs in hepatocellular carcinoma. Hepatology 47: 897–907.

Calin GA, Dumitru CD, Shimizu M et al. (2002) Frequent deletions and down‐regulation of micro‐RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the USA 99: 15524–15529.

Calin GA, Ferracin M, Cimmino A et al. (2005) A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. New England Journal of Medicine 353: 1793–1801.

Calin GA, Liu CG, Sevignani C et al. (2004) MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proceedings of the National Academy of Sciences of the USA 101: 11755–11760.

Chen X, Ba Y, Ma L et al. (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Research 18: 997–1006.

Cimmino A, Calin GA, Fabbri M et al. (2005) miR‐15 and miR‐16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the USA 102: 13944–13949.

Doleshal M, Magotra AA, Choudhury B et al. (2008) Evaluation and validation of total RNA extraction methods for microRNA expression analyses in formalin‐fixed, paraffin‐embedded tissues. Journal of Molecular Diagnostics 10: 203–211.

Droge P and Davey CA (2008) Do cells let‐7 determine stemness? Cell Stem Cell 2: 8–9.

Ebert MS, Neilson JR and Sharp PA (2007) MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nature Methods 4: 721–726.

Esquela‐Kerscher A, Trang P, Wiggins JF et al. (2008) The let‐7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 7: 759–764.

Ferracin M, Veronese A and Negrini M (2010) Micromarkers: miRNAs in cancer diagnosis and prognosis. Expert Review of Molecular Diagnostics 10: 297–308.

Forman JJ, Legesse‐Miller A and Coller HA (2008) A search for conserved sequences in coding regions reveals that the let‐7 microRNA targets Dicer within its coding sequence. Proceedings of the National Academy of Sciences of the USA 105: 14879–14884.

Gallardo E, Navarro A, Vinolas N et al. (2009) miR‐34a as a prognostic marker of relapse in surgically resected non‐small‐cell lung cancer. Carcinogenesis 30(11): 1903–1909.

Garzon R, Calin GA and Croce CM (2009a) MicroRNAs in cancer. Annual Review of Medicine 60: 167–179.

Garzon R, Liu S, Fabbri M et al. (2009b) MicroRNA‐29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113: 6411–6418.

Gramantieri L, Fornari F, Ferracin M et al. (2009) MicroRNA‐221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clinical Cancer Research 15: 5073–5081.

He L, He X, Lowe SW and Hannon GJ (2007) microRNAs join the p53 network – another piece in the tumour‐suppression puzzle. Nature Reviews Cancer 7: 819–822.

He L, Thomson JM, Hemann MT et al. (2005) A microRNA polycistron as a potential human oncogene. Nature 435: 828–833.

Ji J, Shi J, Budhu A et al. (2009) MicroRNA expression, survival, and response to interferon in liver cancer. New England Journal of Medicine 361: 1437–1447.

Johnson SM, Grosshans H, Shingara J et al. (2005) RAS is regulated by the let‐7 microRNA family. Cell 120: 635–647.

Kan T, Sato F, Ito T et al. (2009) The miR‐106b‐25 polycistron, activated by genomic amplification, functions as an oncogene by suppressing p21 and Bim. Gastroenterology 136: 1689–1700.

Klein U, Lia M, Crespo M et al. (2010) The DLEU2/miR‐15a/16‐1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17: 28–40.

Kota J, Chivukula RR, O'Donnell KA et al. (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137: 1005–1017.

Krichevsky AM and Gabriely G (2009) miR‐21: a small multi‐faceted RNA. Journal of Cellular and Molecular Medicine 13: 39–53.

Krutzfeldt J, Rajewsky N, Braich R et al. (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438: 685–689.

Lanford RE, Hildebrandt‐Eriksen ES, Petri A et al. (2010) Therapeutic silencing of microRNA‐122 in primates with chronic hepatitis C virus infection. Science 327: 198–201.

Lawrie CH, Gal S, Dunlop HM et al. (2008) Detection of elevated levels of tumour‐associated microRNAs in serum of patients with diffuse large B‐cell lymphoma. British Journal of Haematology 141: 672–675.

Lee RC, Feinbaum RL and Ambros V (1993) The C. elegans heterochronic gene lin‐4 encodes small RNAs with antisense complementarity to lin‐14. Cell 75: 843–854.

Lu J, Getz G, Miska EA et al. (2005) MicroRNA expression profiles classify human cancers. Nature 435: 834–838.

Ma L, Reinhardt F, Pan E et al. (2010) Therapeutic silencing of miR‐10b inhibits metastasis in a mouse mammary tumor model. Nature Biotechnology 28: 341–347.

Mitchell PS, Parkin RK, Kroh EM et al. (2008) Circulating microRNAs as stable blood‐based markers for cancer detection. Proceedings of the National Academy of Sciences of the USA 105: 10513–10518.

Mraz M, Malinova K, Kotaskova J et al. (2009) miR‐34a, miR‐29c and miR‐17‐5p are downregulated in CLL patients with TP53 abnormalities. Leukemia 23: 1159–1163.

Muller DW and Bosserhoff AK (2008) Integrin beta 3 expression is regulated by let‐7a miRNA in malignant melanoma. Oncogene 27: 6698–6706.

Nicoloso MS, Sun H, Spizzo R et al. (2010) Single‐nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Research 70: 2789–2798.

Ota A, Tagawa H, Karnan S et al. (2004) Identification and characterization of a novel gene, C13orf25, as a target for 13q31–q32 amplification in malignant lymphoma. Cancer Research 64: 3087–3095.

Park SM, Shell S, Radjabi AR et al. (2007) Let‐7 prevents early cancer progression by suppressing expression of the embryonic gene HMGA2. Cell Cycle 6: 2585–2590.

Rybak A, Fuchs H, Smirnova L et al. (2008) A feedback loop comprising lin‐28 and let‐7 controls pre‐let‐7 maturation during neural stem‐cell commitment. Nature Cell Biology 10: 987–993.

Sampson VB, Rong NH, Han J et al. (2007) MicroRNA let‐7a down‐regulates MYC and reverts MYC‐induced growth in Burkitt lymphoma cells. Cancer Research 67: 9762–9770.

Schultz J, Lorenz P, Gross G, Ibrahim S and Kunz M (2008) MicroRNA let‐7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage‐independent growth. Cell Research 18: 549–557.

Si ML, Zhu S, Wu H et al. (2007) miR‐21‐mediated tumor growth. Oncogene 26: 2799–2803.

Takamizawa J, Konishi H, Yanagisawa K et al. (2004) Reduced expression of the let‐7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Research 64: 3753–3756.

Viswanathan SR, Daley GQ and Gregory RI (2008) Selective blockade of microRNA processing by Lin28. Science 320: 97–100.

Viswanathan SR, Powers JT, Einhorn W et al. (2009) Lin28 promotes transformation and is associated with advanced human malignancies. Nature Genetics 41: 843–848.

Volinia S, Calin GA, Liu CG et al. (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proceedings of the National Academy of Sciences of the USA 103: 2257–2261.

West JA, Viswanathan SR, Yabuuchi A et al. (2009) A role for Lin28 in primordial germ‐cell development and germ‐cell malignancy. Nature 460: 909–913.

Yamamoto Y, Kosaka N, Tanaka M et al. (2009) MicroRNA‐500 as a potential diagnostic marker for hepatocellular carcinoma. Biomarkers 14(7): 529–538.

Yu F, Yao H, Zhu P et al. (2007) let‐7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131: 1109–1123.

Yu SL, Chen HY, Chang GC et al. (2008) MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13: 48–57.

Further Reading

Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.

Calin GA and Croce CM (2006) MicroRNA signatures in human cancers. Nature Reviews Cancer 6: 857–866.

Cho WCS (ed.) (2011) MicroRNAs in Cancer Translational Research. Berlin: Springer.

Cortez MA, Bueso‐Ramos C, Ferdin J et al. (2011) MicroRNAs in body fluids – the mix of hormones and biomarkers. Nature Reviews Clinicial Oncology 8: 467–477.

Croce CM (2009) Causes and consequences of microRNA dysregulation in cancer. Nature Reviews Genetics 10: 704–714.

Esquela‐Kerscher A and Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nature Reviews Cancer 6: 259–269.

Lovat F, Valeri N and Croce CM (2011) MicroRNAs in the pathogenesis of cancer. Seminars in Oncology 38: 724–733.

Lujambio A and Esteller M (2007) CpG island hypermethylation of tumor suppressor microRNAs in human cancer. Cell Cycle 6: 1455–1459.

Sandhu S and Garzon R (2011) Potential applications of microRNAs in cancer diagnosis, prognosis, and treatment. Seminars in Oncology 38: 781–787.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Ferracin, Manuela, and Negrini, Massimo(Apr 2012) MicroRNAs and Their Role in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021434]