A zebrafish model of intrahepatic cholangiocarcinoma by dual expression of hepatitis B virus X and hepatitis C virus core protein in liver

Authors

  • Wangta Liu,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    Search for more papers by this author
    • These authors contributed equally to the study.

  • Jim-Ray Chen,

    1. Department of Pathology, Chang Gung Memorial Hospital, Keelung, Taiwan
    2. College of Medicine, Chang Gung Univeristy, Taoyuan, Taiwan
    Search for more papers by this author
  • Chih-Hao Hsu,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    2. Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan
    Search for more papers by this author
  • Yen-Hsing Li,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    Search for more papers by this author
  • Yi-Meng Chen,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    2. Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan
    3. Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Chien-Yuan Lin,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    2. Institute of Microbiology and Biochemistry, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Shin-Jie Huang,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    2. Institute of Microbiology and Biochemistry, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Zen-Kuei Chang,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    Search for more papers by this author
  • Yen-Chun Chen,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    Search for more papers by this author
  • Chi-Hsueh Lin,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    2. Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan
    Search for more papers by this author
  • Hong-Yi Gong,

    1. Department of Aquaculture, and Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan
    Search for more papers by this author
  • Ching-Chun Lin,

    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    Search for more papers by this author
  • Koichi Kawakami,

    1. Division of Molecular and Developmental Biology, National Institute of Genetics, and Department of Genetics, Graduate University for Advanced Studies (SOKENDAI), Mishima, Shizuoka, Japan
    Search for more papers by this author
  • Jen-Leih Wu

    Corresponding author
    1. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
    2. Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan
    3. Institute of Microbiology and Biochemistry, National Taiwan University, Taipei, Taiwan
    • Laboratory of Marine Molecular Biology and Biotechnology, Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan

    Search for more papers by this author
    • fax: +886 2 27824595


  • Potential conflict of interest: Nothing to report.

  • Supported by grants from Academia Sinica, Taiwan. The Taiwan Mouse Clinic is funded by the National Research Program for Biopharmaceuticals (NRPB) at the National Science Council (NSC) of Taiwan.

Abstract

The mechanisms that mediate the initiation and development of intrahepatic cholangiocarcinoma (ICC) associated with hepatitis B and C virus (HBV and HCV, respectively) infection remain largely unclear. In this study we conditionally coexpressed hepatitis B virus X (HBx) and hepatitis C virus core (HCP) proteins in zebrafish livers, which caused fibrosis and consequently contributed to ICC formation at the age of 3 months. Suppressing the transgene expression by doxycycline (Dox) treatment resulted in the loss of ICC formation. The biomarker networks of zebrafish ICC identified by transcriptome sequencing and analysis were also frequently involved in the development of human neoplasms. The profiles of potential biomarker genes of zebrafish ICC were similar to those of human cholangiocarcinoma. Our data also showed that the pSmad3L oncogenic pathway was activated in HBx and HCP-induced ICC and included phosphorylation of p38 mitogen-activated proteinbase (MAPK) and p44/42 mitogen-activated protein kinase (ERK1/2), indicating the association with transforming growth factor beta 1 (TGF-β1) signaling pathway in ICC. Bile duct proliferation, fibrosis, and ICC were markedly reduced by knockdown of TGF-β1 by in vivo morpholinos injections. Conclusion: These results reveal that TGF-β1 plays an important role in HBx- and HCP-induced ICC development. This in vivo model is a potential approach to study the molecular events of fibrosis and ICC occurring in HBV and HCV infection. (HEPATOLOGY 2012;56:2268–2276)

Ancillary