title: A murine model of hepatitis B-associated hepatocellular carcinoma generated by adeno-associated virus-mediated gene delivery.
abstract: A relevant animal model is critical for investigating the pathogenic mechanisms underlying hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC). Mice are not naturally infected by HBV, presumably due to the lack of HBV receptors on mouse hepatocytes. To bypass this entry step of HBV infection, we report generation of a novel HBV model in immunocompetent mice by hepatic delivery of the HBV genome using trans-splicing adeno-associated viral vectors (AAV/HBV). We confirmed production of HBV virions and proteins in the liver and circulation in all AAV/HBV-transduced mice in all four immunocompetent mouse strains tested. These mice produced antigen and antibody profiles similar to that observed in chronic HBV patients. Importantly, 12-16 months later, all 12 AAV/HBV-transduced mice developed macroscopically visible liver-tumor nodules. Ten of the twelve tumors were characterized with typical HCC features. This AAV/HBV-transduced murine HCC model provides a useful instrument for studying the pathogenesis of HBV-associated HCC and the development of HCC therapeutic interventions.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Huang
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Fang
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Ho-Yuan
authors.initials: HY
authors.lastname: Chou
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Pan
authors.forename: Yao-Ming
authors.initials: YM
authors.lastname: Shih
authors.forename: Ping-Yi
authors.initials: PY
authors.lastname: Wu
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Mi-Hua
authors.initials: MH
authors.lastname: Tao
mesh_terms: D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology*; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000150:complications*; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020040:Trans-Splicing; D019562:Viral Load