MicroRNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer

Abstract

Aberrant expression of microRNAs (miRNA) is associated with phenotypes of various cancers, including pancreatic cancer. However, the mechanism of the aberrant expression is largely unknown. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway plays a crucial role in gene expression related to the malignant phenotype of pancreatic cancer. Hence, we studied the role of MAPK in the aberrant expression of miRNAs in pancreatic cancer cells. The alterations in expression of 183 miRNAs induced by activation or inactivation of MAPK were assayed in cultured pancreatic cancer cells and HEK293 cells by means of the quantitative real-time PCR method. We found that four miRNAs, namely, miR-7-3, miR-34a, miR-181d, and miR-193b, were preferentially associated with MAPK activity. Among these miRNAs, miR-7-3 was upregulated by active MAPK, whereas the others were downregulated. Promoter assays indicated that the promoter activities of the host genes of miR-7-3 and miR-34a were both downregulated by alteration in MAPK activity. Exogenous overexpression of the MAPK-associated miRNAs had the effect of inhibition of the proliferation of cultured pancreatic cancer cells; miR-193b was found to exhibit the most remarkable inhibition. A search for target genes of miR-193b led to identification of CCND1, NT5E, PLAU, STARD7, STMN1, and YWHAZ as the targets. Translational suppression of these genes by miR-193b was confirmed by reporter assay. These results indicate that activation of MAPK may play a significant role in aberrant expression of miRNAs and their associated phenotypes in pancreatic cancer. Mol Cancer Res; 10(2); 259-69. Ó2011 AACR.

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

“…As shown in Supplementary Table 3, the 'breast cancer regulation by STMN1' pathway was among those potentially regulated by common differentially expressed miRNAs in PCCs/PGLs. Our results predicted that STMN1 is a potential miR-193b target, and in fact, this regulatory interaction was recently confirmed (Ikeda et al 2012). STMN1 is highly expressed in the developing nervous system and plays a role in axonal elongation and neuronal regeneration (Grenningloh et al 2004), and its overexpression was reported in malignant PCCs/PGLs (Bjorklund et al 2010).…”

Role of microRNA-7 in digestive system malignancy

“…Therefore, there is an urgent need to explore novel therapeutic methods. In accordance with the expression of miR-7 in the pancreas, miR-7-3, which is one of the three endogenous genes potentially transcribed in the human genome, is upregulated by targeting mitogen-activated protein kinase (MAPK), suggesting that miR-7 is negatively modulated by an EGFR-MAPK feedback loop [32] . In an in vitro study, in proliferation and induced apoptosis of CRC cells by directly targeting XRCC2 through decreasing cyclin D1 and increasing p21, caspase-3 and BAX expression [22] .…”

Circulating microRNAs: New biomarkers in diagnosis, prognosis and treatment of cancer (Review)

“…Promoter assays indicated that the promoter activities of the host genes of miRNA-7-3 and miRNA-34a were both down-regulated by alteration in MAPK activity. Exogenous overexpression of the MAPK-associated miRNAs had the effect of inhibition of the proliferation of cultured PaC cells; miRNA-193b was found to exhibit the most remarkable inhibition (149). Regarding circulating miRNAs, the comparative analysis of miRNA expression during malignant progression in the mouse model allows to draw some conclusions about relevant miRNAs in the circulation that can indicate the presence of precursor lesions.…”