title: HCV core inhibits hepatocellular carcinoma cell replicative senescence through downregulating microRNA-138 expression.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Tzu-Yue
authors.initials: TY
authors.lastname: Shiu
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yu-Lueng
authors.initials: YL
authors.lastname: Shih
authors.affiliation: Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: An-Chieh
authors.initials: AC
authors.lastname: Feng
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Hsuan-Hwai
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Tien-Yu
authors.initials: TY
authors.lastname: Huang
authors.affiliation: Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chung-Bao
authors.initials: CB
authors.lastname: Hsieh
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Wei-Kuo
authors.initials: WK
authors.lastname: Chang
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. tyh1216@ms46.hinet.net.
authors.forename: Tsai-Yuan
authors.initials: TY
authors.lastname: Hsieh
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D015536:Down-Regulation; D016174:Hepacivirus; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D019098:Telomerase / Q000235:genetics*; D014758:Viral Core Proteins / Q000235:genetics*
chemical_list: C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D010446:Peptide Fragments; D012333:RNA, Messenger; D014758:Viral Core Proteins; C509186:TERT protein, human; D019098:Telomerase
keywords: Hepatitis C virus; Hepatocellular carcinoma; MicroRNA; Telomerase reverse transcriptase