MicroRNAs (miRNAs) constitute a robust regulatory network with post-transcriptional regulatory efficiency for almost one half of human coding genes, including oncogenes and tumour suppressors. We determined the expression profile of 667 miRNAs in colorectal cancer (CRC) tissues and paired non-tumoural tissues and identified 42 differentially expressed miRNAs. We chose miR-215, miR-375, miR-378, miR-422a and miR-135b for further validation on an independent cohort of 125 clinically characterized CRC patients and for in vitro analyses. MiR-215, miR-375, miR-378 and miR-422a were significantly decreased, whereas miR-135b was increased in CRC tumour tissues. Levels of miR-215 and miR-422a correlated with clinical stage. MiR-135b was associated with higher pre-operative serum levels of CEA and CA19-9. In vitro analyses showed that ectopic expression of miR-215 decreases viability and migration, increases apoptosis and promotes cell cycle arrest in DLD-1 and HCT-116 colon cancer cell lines. Similarly, overexpression of miR-375 and inhibition of miR-135b led to decreased viability. Finally, restoration of miR-378, miR-422a and miR-375 inhibited G1/S transition. These findings indicate that miR-378, miR-375, miR-422a and miR-215 play an important role in CRC as tumour suppressors, whereas miR-135b functions as an oncogene; both groups of miRNA contribute to CRC pathogenesis.

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic

See more in PubMed

Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011. CA Cancer J Clin. 2011;61:212–36. PubMed

Janga SC, Vallabhaneni S. MicroRNAs as post-transcriptional machines and their interplay with cellular networks. Adv Exp Med Biol. 2011;722:59–74. PubMed

Wang Y, Lee CG. MicroRNA and cancer – focus on apoptosis. J Cell Mol Med. 2009;13:12–23. PubMed PMC

Slaby O, Svoboda M, Michalek J, et al. MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer. 2009;8:102. PubMed PMC

Slaby O, Svoboda M, Fabian P, et al. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology. 2007;72:397–402. PubMed

Schepeler T, Reinert JT, Ostenfeld MS, et al. Diagnostic and prognostic microRNAs in stage II colon cancer. Cancer Res. 2008;68:6416–24. PubMed

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

Schetter AJ, Leung SY, Sohn JJ, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA. 2008;299:425–36. PubMed PMC

Bandrés E, Cubedo E, Agirre X, et al. Identification by real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 2006;5:29. PubMed PMC

Earle JSL, Luthra R, Romans A, et al. Association of microRNA expression with microsatellite instability status in colorectal adenocarcinoma. J Mol Diagn. 2010;12:433–40. PubMed PMC

Koga Y, Yasunaga M, Takahashi A, et al. MicroRNA expression profiling of exfoliated colonocytes isolated from feces for colorectal cancer screening. Cancer Prev Res. 2010;3:1435–42. PubMed

Díaz R, Silva J, García JM, et al. Deregulated expression of miR-106a predicts survival in human colon cancer patients. Genes Chromosom Cancer. 2008;47:794–802. PubMed

Ng EKO, Chong WWS, Jin H, et al. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut. 2009;58:1375–81. PubMed

Pu X-xiang, Huang G-liang, Guo H-qiang, et al. Circulating miR-221 directly amplified from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is correlated with p53 expression. J Gastroenterol Hepatol. 2010;25:1674–80. PubMed

Wang L-G, Gu J. Serum microRNA-29a is a promising novel marker for early detection of colorectal liver metastasis. Cancer Epidemiol. 2011 doi: 10.1016/j.canep.2011.05.002. PubMed DOI

Reimers M, Carey VJ. Bioconductor: an open source framework for bioinformatics and computational biology. Methods Enzymol. 2006;411:119–134. PubMed

Miko E, Czimmerer Z, Csánky E, et al. Differentially expressed microRNAs in small cell lung cancer. Exp Lung Res. 2009;35:646–64. PubMed

Hannafon BN, Sebastiani P, de las Morenas A, et al. Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer. Breast Cancer Res. 2011;13:R24. PubMed PMC

Schaefer A, Jung M, Mollenkopf H-J, et al. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer. 2010;126:1166–76. PubMed

Nagel R, le Sage C, Diosdado B, et al. Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res. 2008;68:5795–802. PubMed

Chang KH, Miller N, Kheirelseid EAH, et al. MicroRNA signature analysis in colorectal cancer: identification of expression profiles in stage II tumors associated with aggressive disease. Int J Colorectal Dis. 2011;26:1415–22. PubMed

Paun BC, Cheng Y, Leggett BA, et al. Screening for microsatellite instability identifies frequent 3′-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors. PLoS One. 2009;4:e7715. PubMed PMC

Bitarte N, Bandres E, Boni V, et al. MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells. Stem Cells. 2011;29:1661–71. PubMed

Wang YX, Zhang XY, Zhang BF, et al. Initial study of microRNA expression profiles of colonic cancer without lymph node metastasis. J Dig Dis. 2010;11:50–4. PubMed

Kalimutho M, Del Vecchio Blanco G, Di Cecilia S, et al. Differential expression of miR-144* as a novel fecal-based diagnostic marker for colorectal cancer. J Gastroenterol. 2011;46:1391–402. PubMed

Liu L, Chen L, Xu Y, et al. MicroRNA-195 promotes apoptosis and suppresses tumorigenicity of human colorectal cancer cells. Biochem Biophys Res Commun. 2010;400:236–40. PubMed

Sundaram P, Hultine S, Smith LM, et al. p53-responsive miR-194 inhibits thrombospondin-1 and promotes angiogenesis in colon cancers. Cancer Res. 2011;71:7490–501. PubMed PMC

Xi Y, Formentini A, Chien M, et al. Prognostic values of microRNAs in colorectal cancer. Biomark Insights. 2006;2:113–21. PubMed PMC

Strillacci A, Griffoni C, Sansone P, et al. MiR-101 downregulation is involved in cyclooxygenase-2 overexpression in human colon cancer cells. Exp Cell Res. 2009;315:1439–47. PubMed

Michael MZ, O’ Connor SM, van Holst Pellekaan NG, et al. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003;1:882–91. PubMed

Cho WCS, Chow ASC, Au JSK. MiR-145 inhibits cell proliferation of human lung adenocarcinoma by targeting EGFR and NUDT1. RNA Biol. 2011;8:125–31. PubMed

Sachdeva M, Mo Y-Y. miR-145-mediated suppression of cell growth, invasion and metastasis. Am J Transl Res. 2010;2:170–80. PubMed PMC

Boominathan L. The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network. Cancer Metastasis Rev. 2010;29:613–39. PubMed

Braun CJ, Zhang X, Savelyeva I, et al. p53-responsive microRNAs 192 and 215 are capable of inducing cell cycle arrest. Cancer Res. 2008;68:10094–104. PubMed PMC

Karaayvaz M, Pal T, Song B, et al. Prognostic significance of miR-215 in colon cancer. Clin Colorectal Cancer. 2011;10:340–7. PubMed PMC

Necela BM, Carr JM, Asmann YW, Thompson EA. Differential expression of microRNAs in tumours from chronically inflamed or genetic (APC(Min/+)) models of colon cancer. PLoS One. 2011;6:e18501. PubMed PMC

Tsukamoto Y, Nakada C, Noguchi T, et al. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 2010;70:2339–49. PubMed

MiR-215-5p Reduces Liver Metastasis in an Experimental Model of Colorectal Cancer through Regulation of ECM-Receptor Interactions and Focal Adhesion

MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9

MicroRNA expression profile associated with response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients