title: Repeated hepatocyte injury promotes hepatic tumorigenesis in hepatitis C virus transgenic mice.
abstract: Although hepatitis C virus (HCV) is a well-known causative agent of hepatocellular carcinoma (HCC), the mechanism by which HCV induces HCC remains obscure. To elucidate the role of HCV in hepatocarcinogenesis, a model of hepatocyte injury was established using HCV core transgenic mice, which were developed using C57BL/6 mice transfected with the HCV core gene under control of the serum amyloid P component promoter. After 18-24 months, neither steatosis nor hepatic tumors were found in transgenic mice. The extent of hepatocyte injury and tumorigenesis were then examined in transgenic mice following repeated administration of carbon tetrachloride (CCl(4)) using various protocols (20%, 1/week; 10%, 2/week and 20%, 2/week). Serum alanine aminotransferase (ALT) levels did not differ among HCV core transgenic mice and non-transgenic littermates; however, after 40 weeks, hepatic adenomas preferentially developed in transgenic mice receiving 20% CCl(4) once weekly. Moreover, HCC was observed in transgenic mice receiving 2 weekly injections of a 20% solution of CCl(4), and was not observed in the non-transgenic control mice. In conclusion, the HCV core protein did not promote hepatic steatosis or tumor development in the absence of hepatotoxicity. However, the HCV core protein promoted adenoma and HCC development in transgenic mice following repeated CCl(4) administration. These results suggest that hepatotoxicity resulting in an increased rate of hepatocyte regeneration enhances hepatocarcinogenesis in HCV-infected livers. Furthermore, this experimental mouse model provides a valuable method with which to investigate hepatocarcinogenesis.
authors.affiliation: Department of Microbiology, Tokyo Metropolitan Institute for Neuroscience, Fucyu, Tokyo 183-8526, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Kato
authors.forename: Michiko
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Date
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yasui
authors.forename: Choji
authors.initials: C
authors.lastname: Taya
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yonekawa
authors.forename: Chiharu
authors.initials: C
authors.lastname: Ohue
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yagi
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Hirano
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
mesh_terms: D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D017931:DNA Primers; D005260:Female; D016678:Genome; D016174:Hepacivirus / Q000235:genetics* / Q000302:isolation & purification; D022781:Hepatocytes / Q000473:pathology* / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D014758:Viral Core Proteins / Q000235:genetics / Q000302:isolation & purification
chemical_list: D017931:DNA Primers; D014758:Viral Core Proteins