These authors contributed equally to the study.
Article first published online: 4 DEC 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 6, pages 2268–2276, December 2012
How to Cite
Liu, W., Chen, J.-R., Hsu, C.-H., Li, Y.-H., Chen, Y.-M., Lin, C.-Y., Huang, S.-J., Chang, Z.-K., Chen, Y.-C., Lin, C.-H., Gong, H.-Y., Lin, C.-C., Kawakami, K. and Wu, J.-L. (2012), A zebrafish model of intrahepatic cholangiocarcinoma by dual expression of hepatitis B virus X and hepatitis C virus core protein in liver. Hepatology, 56: 2268–2276. doi: 10.1002/hep.25914
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.
- Issue published online: 4 DEC 2012
- Article first published online: 4 DEC 2012
- Accepted manuscript online: 22 JUN 2012 03:59AM EST
- Manuscript Accepted: 9 JUN 2012
- Manuscript Received: 4 SEP 2011
- Academia Sinica, Taiwan
- National Research Program for Biopharmaceuticals (NRPB) at the National Science Council (NSC) of Taiwan
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)