title: Downregulation of miRNA-30c and miR-203a is associated with hepatitis C virus core protein-induced epithelial-mesenchymal transition in normal hepatocytes and hepatocellular carcinoma cells.
abstract: Hepatitis C virus (HCV) Core protein has been demonstrated to induce epithelial-mesenchymal transition (EMT) and is associated with cancer progression of hepatocellular carcinoma (HCC). However, how the Core protein regulates EMT is still unclear. In this study, HCV Core protein was overexpressed by an adenovirus. The protein levels of EMT markers were measured by Western blot. The xenograft animal model was established by inoculation of HepG2 cells. Results showed that ectopic expression of HCV core protein induced EMT in L02 hepatocytes and HepG2 tumor cells by upregulating vimentin, Sanl1, and Snal2 expression and downregulating E-cadherin expression. Moreover, Core protein downregulated miR-30c and miR-203a levels in L02 and HepG2 cells, but artificial expression of miR-30c and miR-203a reversed Core protein-induced EMT. Further analysis showed that ectopic expression of HCV core protein stimulated cell proliferation, inhibited apoptosis, and increased cell migration, whereas artificial expression of miR-30c and miR-203a significantly reversed the role of Core protein in these cell functions in L02 and HepG2 cells. In the HepG2 xenograft tumor models, artificial expression of miR-30c and miR-203a inhibited EMT and tumor growth. Moreover, L02 cells overexpressing Core protein can form tumors in nude mice. In HCC patients, HCV infection significantly shortened patients' survival time, and loss of miR-30c and miR-203 expression correlated with poor survival. In conclusion, HCV core protein downregulates miR-30c and miR-203a expression, which results in activation of EMT in normal hepatocytes and HCC tumor cells. The Core protein-activated-EMT is involved in the carcinogenesis and progression of HCC. Loss of miR-30c and miR-203a expression is a marker for the poor prognosis of HCC.
authors.affiliation: Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha 410008, PR China.
authors.forename: Dongjing
authors.initials: D
authors.lastname: Liu
authors.affiliation: Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha 410008, PR China. Electronic address: 6296082@qq.com.
authors.forename: Jilin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Medical Service, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, PR China.
authors.forename: Meizhou
authors.initials: M
authors.lastname: Liu
authors.affiliation: Staff's Hospital, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yin
authors.affiliation: Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha 410008, PR China.
authors.forename: Jiantai
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Ultrasonography, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China. Electronic address: zhangbo8095@126.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D014758:Viral Core Proteins / Q000378:metabolism*
chemical_list: C575934:MIRN203 microRNA, mouse; D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus
keywords: Epithelial–mesenchymal transition; Hepatitis C virus core protein; Hepatocellular carcinoma; miRNA