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

• Published in: Hepatology (Baltimore, Md.) Vol. 56; no. 6; pp. 2268 - 2276
• Main Authors: Liu, Wangta, Chen, Jim-Ray, Hsu, Chih-Hao, Li, Yen-Hsing, Chen, Yi-Meng, Lin, Chien-Yuan, Huang, Shin-Jie, Chang, Zen-Kuei, Chen, Yen-Chun, Lin, Chi-Hsueh, Gong, Hong-Yi, Lin, Ching-Chun, Kawakami, Koichi, Wu, Jen-Leih
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-12-2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Animals; Animals, Genetically Modified; Anti-Bacterial Agents - pharmacology; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - pathology; Bile Ducts, Intrahepatic; Biological and medical sciences; Cholangiocarcinoma - genetics; Cholangiocarcinoma - pathology; Connective Tissue Growth Factor - genetics; Cyclin D1 - genetics; Disease Models, Animal; Doxycycline - pharmacology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression - drug effects; Hepacivirus; Hepatitis; Hepatitis B; Hepatitis C; Hepatology; Kinases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; MAP Kinase Signaling System; Medical sciences; Mitogen-Activated Protein Kinase 3 - genetics; p38 Mitogen-Activated Protein Kinases - genetics; Proteins; Smad2 Protein - genetics; Smad3 Protein - genetics; Trans-Activators - genetics; Transforming Growth Factor beta1 - genetics; Tumors; Up-Regulation; Vascular Endothelial Growth Factor A - genetics; Viral Core Proteins - genetics; Zebrafish; Zebrafish Proteins - genetics; Liver; Orthohepadnavirus; Hepatic disease; Malignant tumor; Biliary tract disease; Protein; Virus; Hepadnaviridae; Malignant cholangioma; Gastroenterology; Digestive diseases; Models; Intrahepatic; Hepatitis B virus; Flaviviridae; Hepatitis C virus; Hepacivirus; Cancer
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.25914

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)