MicroRNA-451: epithelial-mesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma

// Jia-Yuan Huang 1,* , Kai Zhang 1,* , Dong-Qin Chen 1,* , Jing Chen 1 , Bing Feng 1 , Haizhu Song 1 , Yitian Chen 1 , Ziman Zhu 2 , Lei Lu 3 , Wei De 4 , Rui Wang 1 and Long-Bang Chen 1 1 Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China 2 Department of Hepatobiliary Surgery, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China 3 Liver Disease Center of PLA, The 81th Hospital of PLA, Nanjing, Jiangsu, China 4 Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China * These authors have contributed equally to this work Correspondence to: Rui Wang, email: // Long-Bang Chen, email: // Keywords : hepatocellular carcinoma, miR-451, c-Myc, epithelial-mesenchymal transition, invasion Received : December 12, 2014 Accepted : May 12, 2015 Published : May 27, 2015 Abstract Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays critical roles in malignant transformation and tumor progression. Previously, we have shown that microRNA-451 (miR-451) inhibits growth, increases chemo- or radiosensitivity and reverses epithelial to mesenchymal transition (EMT) in lung cancer. However, the roles of miR-451 in hepatocelluar carcinoma (HCC) progression and metastasis are still largely unknown. Reduced miR-451 in HCC tissues was observed to be significantly correlated with advanced clinical stage, metastasis and worse disease-free or overall survival. Through gain- and loss-of function experiments, we demonstrated that miR-451 inhibited cell growth, induced G0/G1 arrest and promoted apoptosis in HCC cells. Importantly, miR-451 could inhibit the migration and invasion in vitro , as well as in vivo metastasis of HCC cells through regulating EMT process. Moreover, the oncogene c-Myc was identified as a direct and functional target of miR-451 in HCC cells. Knockdown of c-Myc phenocopied the effects of miR-451 on EMT and metastasis of HCC cells, whereas overexpression of c-Myc partially attenuated the functions of miR-451 restoration. Furthermore, miR-451 downregulation-induced c-Myc overexpression leads to the activation of Erk1/2 signaling, which induces acquisition of EMT phenotype through regulation of GSK-3β/snail/E-cadherin and the increased expression of MMPs family members in HCC cells. Collectively, these data demonstrated that miR-451 is a novel prognostic biomarker for HCC patients and that function as a potential metastasis inhibitor in HCC cells through activation of the Erk1/2 signaling, at least partially by targeting c-Myc. Thus, targeting miR-451/c-Myc/Erk1/2 axis may be a potential strategy for the treatment of metastatic HCC.