miR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Met


Korhan P., Erdal E., Atabey N.

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol.450, no.4, pp.1304-1312, 2014 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 450 Issue: 4
  • Publication Date: 2014
  • Doi Number: 10.1016/j.bbrc.2014.06.142
  • Journal Name: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.1304-1312
  • Keywords: Hepatocellular carcinoma, miR-181a-5p, c-Met, Motility/invasion, Branching-morphogenesis, MICRORNAS, MECHANISMS, EXPRESSION, PROGNOSIS, THERAPY
  • Dokuz Eylül University Affiliated: Yes

Abstract

c-Met receptor tyrosine kinase has been regarded as a promising therapeutic target for hepatocellular carcinoma (HCC). Recently, microRNAs (miRNAs) have been shown as a novel mechanism to control c-Met expression in cancer. In this study, we investigate the potential contribution of miR-181a-5p dysregulation to the biology of c-Met overexpression in HCC. Herein, we found an inverse expression pattern between miR-181a-5p and c-Met expression in normal, cirrhotic and HCC liver tissues. Luciferase assay confirmed that miR-181a-5p binding to the 3'-UTR of c-Met downregulated the expression of c-Met in HCC cells. Overexpression of miR-181a-5p suppressed both HGF-independent and -dependent activation of c-Met and consequently diminished branching-morphogenesis and invasion. Combined treatment with miR-181a-5p and c-Met inhibitor led to a further inhibition of c-Met-driven cellular activities. Knockdown of miR-181a-5p promoted HGF-independent/-dependent signaling of c-Met and accelerated migration, invasion and branching-morphogenesis. In conclusion, our results demonstrated for the first time that c-Met is a functional target gene of miR-181a-5p and the loss of miR-181a-5p expression led to the activation of c-Met-mediated oncogenic signaling in hepatocarcinogenesis. These findings display a novel molecular mechanism of c-Met regulation in HCC and strategies to increase miR-181a5p level might be an alternative approach for the enhancement of the inhibitory effects of c-Met inhibitors. (C) 2014 Elsevier Inc. All rights reserved.