Characterization of global microRNA expression reveals oncogenic potential of miR-145 in metastatic colorectal cancer

Abstract

BackgroundMicroRNAs (MiRNAs) are short non-coding RNAs that control protein expression through various mechanisms. Their altered expression has been shown to be associated with various cancers. The aim of this study was to profile miRNA expression in colorectal cancer (CRC) and to analyze the function of specific miRNAs in CRC cells. MirVana miRNA Bioarrays were used to determine the miRNA expression profile in eight CRC cell line models, 45 human CRC samples of different stages, and four matched normal colon tissue samples. SW620 CRC cells were stably transduced with miR-143 or miR-145 expression vectors and analyzed in vitro for cell proliferation, cell differentiation and anchorage-independent growth. Signalling pathways associated with differentially expressed miRNAs were identified using a gene set enrichment analysis.ResultsThe expression analysis of clinical CRC samples identified 37 miRNAs that were differentially expressed between CRC and normal tissue. Furthermore, several of these miRNAs were associated with CRC tumor progression including loss of miR-133a and gain of miR-224. We identified 11 common miRNAs that were differentially expressed between normal colon and CRC in both the cell line models and clinical samples. In vitro functional studies indicated that miR-143 and miR-145 appear to function in opposing manners to either inhibit or augment cell proliferation in a metastatic CRC model. The pathways targeted by miR-143 and miR-145 showed no significant overlap. Furthermore, gene expression analysis of metastatic versus non-metastatic isogenic cell lines indicated that miR-145 targets involved in cell cycle and neuregulin pathways were significantly down-regulated in the metastatic context.ConclusionMiRNAs showing altered expression at different stages of CRC could be targets for CRC therapies and be further developed as potential diagnostic and prognostic analytes. The identified biological processes and signalling pathways collectively targeted by co-expressed miRNAs in CRC provide a basis for understanding the functional role of miRNAs in cancer.

MicroRNA profiling differentiates colorectal cancer according to KRAS status

“…We identified 19 new miRNAs deregulated in CRC ( Table 1) that, to our knowledge, have never before been reported in cancer. We found deregulation of miR-1, miR-195, miR-143, miR-215, miR-31, miR-194, miR-30c, miR-133b, miR-192, miR-30b, miR-378*, miR-137, miR-133a, and miR-378 in CRC, which is consistent with earlier reports of miRNA expression in CRC (Michael et al, 2003;Bandres et al, 2006;Cummins et al, 2006;Volinia et al, 2006;Monzo et al, 2008;Arndt et al, 2009;Earle et al, 2010;Wang et al, 2010). Down-regulation of miR-378 in CRC compared with normal, observed in both our microarray and RT-PCR analysis, was also seen in a study by Wang et al (2010), who compared para-cancerous tissues and colorectal cancer samples.…”

miRNA-145 Targets v-ets Erythroblastosis Virus E26 Oncogene Homolog 1 to Suppress the Invasion, Metastasis, and Angiogenesis of Gastric Cancer Cells

“…Meanwhile, miR-145 impacts the migration, invasion, and metastasis of cancer cells by targeting mucin 1 (48) and N-cadherin (49), and also affects p53-mediated cell-cycle arrest by targeting p21 (47). On the other hand, miR-145 promotes anchorage-independent growth and exerts an oncogenic effect in metastatic colorectal cancer cells by downregulating E-cadherin (50). In this study, we showed the potential application of miR-145 as a target for the therapeutics of gastric cancer.…”

Advances in epigenetic biomarker research in colorectal cancer

“…For example, miR-34a, miR-191 and miR-378 were reported to be upregulated in some studies [71][72][73] and yet were down regulated in others [74][75][76] . This may have been caused by heterogeneity between the different studies with regards to tumor stage, tumor location, genetic background and technical issues.…”