MicroRNAs in Cancer

Abstract

Initially considered an epiphenomenon, micro ribonucleic acids (also called miRNAs) and other small noncoding RNA molecules are now considered major players in cell biology. MiRNAs regulate gene expression through effects on translation, transcription and chromatin modification. Multiple miRNAs are dysregulated in human cancer and affect cellular proliferation, apoptosis, metastasis and tumour invasion and the phenotype of cancer cells. Virtually every cell type and cancer has a specific miRNA expression pattern. This unique miRNA expression pattern allows the classification of specific cancer types and often gives prognostic information. Profiling based on miRNAs may be more specific and robust than profiling based on mRNAs. MiRNAs can be studied in virtually all tissues including plasma. More work is required, but miRNAs have already improved our understanding of the pathogenesis of cancer and tumour progression and appear promising as novel diagnostic biomarkers. Finally, they may be of value in the development of new genetic treatments.

Key Concepts

  • MicroRNAs regulate gene expression.
  • MicroRNAs are important in the pathogenesis and progression of human cancers.
  • MicroRNAs can function as tumour suppressors and as tumour promoters (oncomirs).
  • Cancers of different origin have specific microRNA expression patterns, allowing molecular characterisation.
  • MicroRNAs can serve as biomarkers for cancer and may become useful for the treatment of cancer.
  • MicroRNA analysis may give prognostic information and be of use in subtyping histologically similar tumours into less and more clinically aggressive categories.
  • Exosomes contain microRNAs and processing enzymes and mediate some of the biological effects of microRNAs.

Keywords: microRNAs; noncoding RNAs; gene profiling; cancer; leukaemia; malignancy; exosomes

Figure 1. Biogenesis and functions of miRNAs (for details see text).
Figure 2. Methods used to study miRNAs (for details see Calin and Croce, and Ferdin et al., ).
close

References

Adams CM, Hiebert SW and Eischen CM (2016) Myc induces miRNA‐mediated apoptosis in response to HDAC inhibition in hematologic malignancies. Cancer Research 76: 736–748.

Alemdehy MF, Haanstra JR, de Looper HW, et al. (2015) ICL induced miR139‐3p and miR199a‐3p have opposite roles in hematopoietic cell expansion and leukemic transformation. Blood 125: 3937–3948.

Balaguer F, Link A, Lozano JJ, et al. (2010) Epigenetic silencing of miR‐137 is an early event in colorectal carcinogenesis. Cancer Research 70: 6609–6618.

Ballabio E, Mitchell T, van Kester MS, et al. (2010) MicroRNA expression in Sézary syndrome: identification, function and diagnostic potential. Blood 116: 1105–1113.

Berindan‐Neagoe I and Calin GA (2014) Molecular pathways: microRNAs, cancer cells, and microenvironment. Clinical Cancer Research 20: 6247–6253.

Bhagat TD, Zhou L, Sokol L, et al. (2013) miR‐21 mediates hematopoietic suppression in MDS by activating TGF‐β signaling. Blood 121: 2875–2881.

Blum W, Garzon R, Klisovic RB, et al. (2010) Clinical response and miR‐29b predictive significance in older AML patients treated with a‐10 day schedule of decitabine. Proceedings of the National Academy of Sciences of the United States of America 107: 7473–7478.

Bovell LC, Shanmugan C, Putcha BD, et al. (2013) The prognostic value of microRNAs varies with patient race/ ethnicity and stage of colorectal cancer. Clinical Cancer Research 19: 3955–3965.

Calin GA, Dumitru C, 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 United States of America 99: 15524–15529.

Calin GA, Sevignani C, Dumitru CD, et al. (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proceedings of the National Academy of Sciences of the United States of America 101: 2999–3004.

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

Calin GA and Croce CM (2007) Investigation of microRNA alterations in leukemias and lymphomas. Methods of Enzymology 427: 193–213.

Calin GA and Croce CM (2009) Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein‐coding genes [review article]. Blood 114: 4761–4770.

Chandradoss SD, Schirle NT, Szczepaniak M, et al. (2015) A dynamic search process underlies microRNA targeting. Cell 162: 96–107.

Chen P, Price C, Li Z, et al. (2013) miR‐9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia rearranged leukemia. Proceedings of the National Academy of Sciences of the United States of America 110: 11511–11516.

Christensen BC, Avissar‐Whiting M, Ouellet LG, et al. (2010) Mature microRNA sequence polymorphism in MIR196A2 is associated with risk and prognosis of head and neck cancer. Clinical Cancer Research 16: 3713–3720.

Cortez MA, Ivan C, Valdecanas D, Niknam S, et al. (2016) PDL1 regulation by p53 via miR‐34. Journal of the National Cancer Institute 108: dvj 303.

Cui B, Chen L, Zhang S, et al. (2014) MicroRNA‐155 influences B‐cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. Blood 124: 546–554.

De Leeuw DC, van den Ancker W, Denkers F, et al. (2013) MicroRNA profiling can classify acute leukemias as either acute myeloid leukemia or acute lymphoid leukemia. Clinical Cancer Research 19: 2187–2196.

Di Leva G, Gasparini P, Piovan C, et al. (2010) MicroRNA cluster 221–222 and estrogen receptor α interactions in breast cancer. Journal of National Cancer Institute 102: 706–721.

Du R, Sun W, Xia L, et al (2012) Hypoxia‐induced down‐regulation of microRNA‐34a promotes EMT by targeting the Notch signaling pathway in tubular epithelial cells. PloS One 7: e30771.

Dvinge H, Git A, Gräf S, et al. (2013) The shaping and functional consequences of the microRNA landscape in breast cancer. Nature 16: 378–382.

Fabbri M, Paone A, Calore F, et al. (2012) MicroRNAs bind to Toll‐like receptors to induce prometastatic inflammatory response. Proceedings of the National Academy of Sciences of the United States of America 109: E2110–E2116.

Ferdin J, Kunej T and Calin GA (2010) Non‐coding RNAs: identification of cancer‐associated microRNAs by gene profiling. Technology in Cancer Research and Treatment 9: 1–16.

Garzon R, Volinia S, Liu CG, et al. (2008) MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 111: 3183–3189.

Garzon R, Heaphy CEA, Havelange V, et al. (2009) MicroRNA29b functions in acute myeloid leukemia. Blood 114: 5331–5341.

Heneghan HM, Miller N, Kelly R, et al. (2010) Systemic miRNA‐195 differentiates breast cancer from other malignancies and is a potential biomarker for detecting noninvasive and early stage disease. The Oncologist 15: 673–682.

Incoronato M, Garofalo M, Urso L, et al. (2010) miR‐212 increases tumor necrosis factor‐related apoptosis‐inducing ligand sensitivity in non‐small cell lung cancer by targeting the antiapoptotic protein PED. Cancer Research 70: 3638–3646.

Iorio MV, Ferracin M, Liu CG, et al. (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Research 65: 7065–7070.

Iorio MV, Casalini P, Piovan C, et al. (2009) MicroRNA‐205 regulates HER3 in human breast cancer. Cancer Research 69: 2195–2200.

Iqbal J, Shen Y, Huang X, et al. (2015) Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B‐cell lymphoma. Blood 125: 1137–1145.

Ito M, Teshima K, Ikeda S, et al. (2014) MicroRNA‐150 inhibits tumor invasion and metastasis by targeting the chemokine receptor CCR6, in advanced cutaneous T‐cell lymphoma. Blood 123: 1499–12511.

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.

Jones K, Nourse JP, Keane C, et al. (2014) Plasma microRNA are didease response biomarkers in classical Hodgkin lymphoma. Clinical Cancer Research 20: 253–264.

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 delivery of miR‐26a inhibits cancer cell proliferation and induces tumor‐specific apoptosis. Cell 137: 1005–1017.

Krol J, Loedige I and Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nature Reviews. Genetics 11: 597–610.

Kulda V, Pesta M, Topolcan O, et al. (2010) Relevance of miR‐21 and miR‐143 expression in tissue samples of colorectal carcinoma and its liver metastases. Cancer Genetics and Cytogenetics 200: 154–160.

Landi MT, Zhao Y, Rotunno M, et al. (2010) MicroRNA expression differentiates histology and predicts survival of lung cancer. Clinical Cancer Research 16: 430–441.

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.

Lebanony D, Benjamin H, Gilad S, et al. (2009) Diagnostic assay based on hsa‐miR‐205 expression distinguishes squamous from nonsquamous non‐small‐cell lung carcinoma. Journal of Clinical Oncology 27: 2030–2037.

Lewis BP, Burge CB and Bartel DP (2005) Conserved seed pairing often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.

Li Y, Guessous F, Zhang Y, et al. (2009) MicroRNA‐34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Research 69: 7569–7576.

Li A, Omura N, Hong SM, et al. (2010) Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR‐200a/200b in association with elevated circulating miR‐200a and miR‐200b levels. Cancer Research 70: 5226–5237.

Lin XJ, Chong Y, Guo ZW, et al. (2015) A serum microRNA classifier for early detection of hepatocellular carcoinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case–control study. Lancet Oncology 16: 804–815.

Liu X, Sempere LF, Ouyang H, et al. (2010) MicroRNA‐31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors. Journal of Clinical Investigation 120: 1298–1309.

Liu X, Liao W, Peng H, et al (2016) MiR‐181a promotes G1/S transition and cell proliferation in pediatric acute myeloid leukemia by targeting ATM. Journal of Cancer Research and Clinical Oncology 42: 77–87.

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

Ma J, Dong C and Ji C (2010) MicroRNA and drug resistance. Cancer Gene Therapy 17: 523–531.

Majid S, Dar AA, Saini S, et al. (2013) miR34‐b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways. Clinical Cancer Research 19: 73–84.

Melo SA, Sugimoto H, O'Connell JT, et al. (2014) Cancer exosomes perform cell‐independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26: 707–721.

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 United States of America 105: 10513–10518.

Mudduluru G, Abba M, Batliner J, et al. (2015) A systematic approach to defining the microRNA landscape in metastasis. Cancer Research 75: 3010–3019.

Navarro A, Diaz T, Martinez A, et al. (2009) Regulation of JAK2 by miR‐135a: prognostic impact in classic Hodgkin lymphoma. Blood 114: 2945–2951.

Navarro A, Clot G, Prieto M, et al. (2013) microRNA expression profiles identify subtypes of mantle cell lymphoma with different clinicobiological characteristics. Clinical Cancer Research 19: 3121–3129.

Ng EKO, Chong WWS, Jin H, et al. (2009) Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 58: 1375–1381.

Nishimura M, Jung EJ, Shah MY, et al. (2013) Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment. Cancer Discovery 3: 1302–1315.

O'Driscoll L (2015) Biologic role of microRNAs and exosomes in cancer. New England Journal of Medicine 372: 2359–2362.

Patel SA and Gooderham NJ (2015) IL6 mediates immune colorectal cancer cell cross‐talk via miR‐21 and miR‐29b. Molecular Cancer Research 13: 1502–1508.

Pichiorri F, Su SS, Ladetto M, et al. (2008) MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 105: 12885–12890.

Pineau P, Volinia S, McJunkin K, et al. (2010) miR‐221 overexpression contributes to liver tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 107: 264–269.

Roccaro AM, Sacco A, Thompson B, et al. (2009) MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood 113: 6669–6680.

Rocci A, Hofmeister CC, Geyer S, et al. (2014) Circulating miRNA markers show promise as new prognosticators for multiple myeloma. Leukemia 28: 1922–1926.

Sahlberg KK, Bottai G, Naume B, et al. (2015) A serum microRNA signature predicts tumor relapse and survival in triple‐negative breast cancer patients. Clinical Cancer Research 21: 1207–1214.

Sarver AL, French AJ, Borralho PM, et al. (2009) Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states. BMC Cancer 9: 401.

Schetter AJ, Leung SY, Sohn JJ, et al. (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299: 425–436.

Sempere LF, Christensen M, Silahtaroglu A, et al. (2007) Altered microRNA expression confined to specific epithelial cell subpopulation in breast cancer. Cancer Research 67: 11612–11620.

Shackelford RE, Mayhall K, Maxwell NM, et al. (2013) Nicotinamide phosphoribosyl‐transferase in malignancy: a review. Genes & Cancer 4: 447–456.

Silva J, García V, Zaballos Â, et al. (2011) Vesicle‐related microRNAs in plasma of NSCLC patients and correlation with survival. European Respiratory Journal Express. 3: 617–623.

Sossey‐Alaoui K and Plow EF (2016) miR‐138‐mediated regulation of KINDLIN‐2 expression modulates sensitivity to chemotherapeutics. Molecular Cancer Research 14: 228–238.

Spizzo R, Nicoloso MS, Croce CM, et al. (2009) SnapShot: microRNAs in cancer. Cell 137: 586e.

Spizzo R, Nicoloso MS, Lupini L, et al. (2010) miR‐145 participates with TP53 in a death‐promoting regulatory loop and targets estrogen receptor‐α in human breast cancer cells. Cell Death and Differentiation 17: 246–254.

Starczynowski DT, Kuchenbauer F, Argiropoulos B, et al. (2010) Identification of miR‐145 and miR‐146a as mediators of the 5q‐syndrome phenotype. Nature Medicine 16: 49–59.

Summerer I, Unger K, Braselmann H, et al. (2015) Circulating microRNAs as prognostic therapy biomarkers in head and neck cancer patients. British Journal of Cancer 113: 76–82.

Tang H, Deng M, Tang Y, et al. (2013) miR200b and miR200c as prognostic factors and mediators of gastric cancer cell progression. Clinical Cancer Research 19: 5602–5612.

Umezu T, Tadokoro H, Azuma K, et al. (2014) Exosomal miR135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor‐inhibiting HIF‐1. Blood 124: 3748–3757.

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 United States of America 103: 2257–2261.

Volinia S and Croce CM (2013) Prognostic microRNA/mRNA signature from the integrated analysis of patients with invasive breast cancer. Proceedings of the National Academy of Sciences of the United States of America 110: 9845–9850.

Wang Y, Gu J, Roth JA, et al. (2013) Pathway‐based serum microRNA profiling and survival in patients with advanced stage non‐small cell lung cancer. Cancer Research 73: 4801–4809.

Wiggins JF, Ruffino L, Kelnar K, et al. (2010) Development of a lung cancer therapeutic based on the tumor suppressor microRNA‐34. Cancer Research 70: 5923–5930.

Yamanaka Y, Tagawa H, Takahashi N, et al. (2009) Aberrant overexpression of microRNAs activate AKT signaling via down‐regulation of tumor suppressors in natural killer‐cell lymphoma/ leukemia. Blood 114: 265–3275.

Yanaihara N, Caplen N, Bowman E, et al. (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9: 189–198.

Zhang C, Tong J and Huang G (2013) Nicotinamide phosphoribosyl transferase (Nampt) is a target of microRNA‐26b in colorectal cancer cells. PloS One 8: e69963.

Zhang L, Zhang S, Yao J, et al. (2015) Microenvironment‐induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527: 1004–1104.

Zhao JJ, Lin J, Lwin T, et al. (2010) microRNA expression profile and identification of miR‐29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Blood 115: 2630–2639.

Zhou Y, Chen L, Barlogie B, et al. (2010) High‐risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2. Proceedings of the National Academy of Sciences of the United States of America 107: 7904–7909.

Further Reading

Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136: 215–233.

Dykxhoorn DM (2010) MicroRNAs and metastasis: little RNAs go a long way. Cancer Research 70: OF1–OF6.

Lawrie CH (2007) MicroRNAs and haematology: small molecules, big function. British Journal of Haematology 137: 503–512.

Lin S and Gregory RI (2015) MicroRNA biogenesis pathways in cancer. Nature Reviews. Cancer 15: 321–333.

Ryan BM, Robles AI and Harris CC (2010) Genetic variations in microRNA networks: the implications for cancer research. Nature Reviews. Cancer 10: 389–402.

Tuna M, Machado AS and Calin GA (2016) Genetic and epigenetic alterations of microRNAs and implications for human cancers and other diseases. Genes, Chromosomes and Cancer 55: 193–214.

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

* Required Field

How to Cite close
Munker, Reinhold, Shackelford, Rodney, and Calin, George A(Aug 2016) MicroRNAs in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023161.pub2]