MicroRNA-199b-5p attenuates TGF-[beta]1-induced epithelial-mesenchymal transition in hepatocellular carcinoma

• Published in: British journal of cancer Vol. 117; no. 2; p. 233
• Main Authors: Zhou, Shao-jun, Liu, Fu-yao, Zhang, An-hong, Liang, Hui-fang, Wang, Ye, Ma, Rong, Jiang, Yuan-hui, Sun, Nian-feng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 11.07.2017
• Subjects: 1-Phosphatidylinositol 3-kinase; 3' Untranslated regions; AKT protein; Biotechnology; Cadherins; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell aggregation; Cell migration; Gene expression; Hepatocellular carcinoma; Liver cancer; Mesenchyme; Metastases; miRNA; Molecular modelling; mRNA; N-Cadherin; Phosphorylation; Rodents; Signal transduction; Tissues; Transforming growth factor-b1; Tumors; Xenografts
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2017.164

Background:Accumulating evidence indicates that N-cadherin is a cell adhesion molecule that has critical roles in tumour progression. However, the role of N-cadherin in hepatocellular carcinoma (HCC) remains controversial.Methods:This study aims to investigate the expression status of N-cadherin and its molecular mechanisms in HCC.Results:The expression of N-cadherin was markedly overexpressed in HCC tissues and cell lines. We identified that miR-199b-5p binds to the 3'-UTR of N-cadherin mRNA, thus decreasing N-cadherin expression in HCC cells. We also found the downregulation of miR-199b-5p in HCC specimens, which was inversely correlated with N-cadherin upregulation, predicted poor clinical outcomes in HCC patients. Next, we determined that miR-199b-5p overexpression promoted cell aggregation, suppressed cell migration and invasion in HCC cells, and inhibited xenografts tumour metastasis in nude mice. Moreover, we demonstrated that miR-199b-5p attenuated TGF-β1 induced epithelial-mesenchymal transition (EMT) -associated traits, while its effects could be partially reversed by N-cadherin restoration. Finally, we examined that N-cadherin downregulation or miR-199b-5p overexpression suppressed TGF-β1-induced Akt phosphorylation, and inhibition of PI3K/Akt pathway blocked TGF-β1-induced N-cadherin overexpression in HCC cells.Conclusions:Our data demonstrate that N-Cadherin was markedly overexpressed and miR-199b-5p was significantly downregulated in HCC. MiR-199b-5p exerts inhibitory effects on EMT, and directly targets N-cadherin in HCC, supporting the potential utility of miR-199b-5p as a promising strategy to treat HCC. Also, a positive regulatory loop exists between N-cadherin and Akt signalling represents a novel mechanism of TGF-β1-mediated EMT in HCC cells.