Journal Article

HCV core inhibits hepatocellular carcinoma cell replicative senescence through downregulating microRNA-138 expression

Feng, An-Chieh, Huang, Shih-Ming, Lin, Hsuan-Hwai, Shiu, Tzu-Yue, Shih, Yu-Lueng, Hsieh, Tsai-Yuan, Huang, Tien-Yu, Hsieh, Chung-Bao, Chang, Wei-Kuo

2017

Overview

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). HCV core protein is considered as a positive regulator of telomerase activity. In this study, we focused on the deregulated microRNA-138 (miR-138) in HCV-associated HCC. Differential expression of miR-138 was determined by TaqMan quantitative real-time PCR. The target gene of miR-138 was verified by luciferase reporter assay, quantitative real-time PCR, and Western blotting. Moreover, three assays based on telomerase activity, cell proliferation, and senescence-associated β-galactosidase activity were performed. The correlation analysis revealed a significantly negative correlation between miR-138 and telomerase reverse transcriptase (TERT) mRNA expression in HCC. Further, we showed that mature HCV core protein of 173 amino acids, but not full-length form of 191 amino acids, suppressed miR-138 expression. TERT was verified as a direct target of miR-138 in HCC cells. Furthermore, TERT-targeting miR-138 supplementation can prevent HCV core protein from repressing HCC cell replicative senescence. Collectively, HCV core protein can enhance TERT protein expression through downregulating TERT-targeting miR-138 expression, which in turn inhibits HCC cell replicative senescence. This study may further help our understanding on the pathogenic mechanisms of HCV core protein in HCV-associated HCC development. Key message miR-138 is downregulated in HCV-associated HCC. Mature HCV core protein plays a pathogenic role in suppressing miR-138 expression. Telomerase reverse transcriptase represents a direct target of miR-138 in HCC cells. miR-138 promotes HCC cell senescence, suggesting potential for HCC treatment.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Amino acids / Biomedical and Life Sciences / Biomedicine / Carcinoma, Hepatocellular - genetics / Cell Line, Tumor / Cell proliferation / Cellular Senescence - genetics / Chronic infection / Cirrhosis / Core protein / Correlation analysis / Down-Regulation / Gene expression / Hepacivirus / Hepatitis / Hepatitis C / Hepatocellular carcinoma / Human Genetics / Humans / Internal Medicine / Liver cancer / Liver cirrhosis / Liver Neoplasms - genetics / MicroRNAs / MicroRNAs - genetics / miRNA / Molecular Medicine / Original Article / Peptide Fragments - genetics / Polymerase chain reaction / Proteins / RNA, Messenger - metabolism / RNA-directed DNA polymerase / Senescence / Supplements / Telomerase / Telomerase - genetics / Telomerase reverse transcriptase / Viral Core Proteins - genetics / Western blotting / β-Galactosidase