title: Hepatitis C virus promotes hepatocellular carcinogenesis by targeting TIPE2, a new regulator of DNA damage response.
abstract: Infection of hepatitis C virus (HCV) is associated with primary hepatocellular carcinoma (HCC). However, its underlying molecular mechanisms remain enigmatic. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a new negative regulator of immunity, plays significant roles in modulating inflammation and tumorigenesis. We hypothesized that TIPE2 might be involved in the development of HCV-induced HCC. To test this hypothesis, the expression of TIPE2 was determined by Western blot in the tumor and pericarcinomatous tissues collected from ten HCV-positive HCC patients; the interaction between TIPE2 and HCV-encoded non-structural proteins was analyzed by immunoprecipitation and immunofluorescence assays, and tumorigenesis and its mechanisms were studied in cell models and nude mice. Our results demonstrated that the expression of TIPE2 was significantly reduced in HCC tissues compared to that in the paracarcinoma tissues. HCV-encoded non-structural protein NS5A could specifically interact with TIPE2 and induce its degradation. Downregulation of TIPE2 by shRNA in cell lines increased genomic DNA damage and promoted cell colony formation in vitro and tumorigenesis in nude mice. In contrast, overexpression of TIPE2 had an opposite effect. Downregulation of TIPE2 by NS5A is associated with genomic DNA instability and HCV-induced HCC development. Thus, TIPE2 may be a new therapeutic target for the treatment of HCV-associated HCC.
authors.affiliation: Henan Key Laboratory of Engineering Antibody Medicine, Medical College of Henan University, Kaifeng, Henan, 475004, China.
authors.forename: Yaohui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Zhengzhou University Affiliated Tumor Hospital, Zhengzhou, Henan, 450001, China.
authors.forename: Jinxue
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Wuhui
authors.initials: W
authors.lastname: Song
authors.affiliation: Henan Key Laboratory of Engineering Antibody Medicine, Medical College of Henan University, Kaifeng, Henan, 475004, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Henan Key Laboratory of Engineering Antibody Medicine, Medical College of Henan University, Kaifeng, Henan, 475004, China.
authors.forename: Mingli
authors.initials: M
authors.lastname: Wang
authors.affiliation: Henan Key Laboratory of Engineering Antibody Medicine, Medical College of Henan University, Kaifeng, Henan, 475004, China.
authors.forename: Jiuge
authors.initials: J
authors.lastname: Chen
authors.affiliation: Henan Key Laboratory of Engineering Antibody Medicine, Medical College of Henan University, Kaifeng, Henan, 475004, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.affiliation: Henan Key Laboratory of Engineering Antibody Medicine, Medical College of Henan University, Kaifeng, Henan, 475004, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Henan Key Laboratory of Engineering Antibody Medicine, Medical College of Henan University, Kaifeng, Henan, 475004, China.
authors.forename: Fanni
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
authors.forename: Youhai H
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Henan Key Laboratory of Engineering Antibody Medicine, Medical College of Henan University, Kaifeng, Henan, 475004, China. mayf@henu.edu.cn.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D049109:Cell Proliferation; D004249:DNA Damage; D005260:Female; D005455:Fluorescent Antibody Technique; D016174:Hepacivirus / Q000472:pathogenicity*; D006526:Hepatitis C / Q000821:virology*; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014407:Tumor Cells, Cultured; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D012324:RNA-Dependent RNA Polymerase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017361:Viral Nonstructural Proteins; C552057:TNFAIP8L2 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: DNA damage response; Hepatitis C virus; Hepatocellular carcinoma; NS5A; TIPE2