A zebrafish model of intrahepatic cholangiocarcinoma by dual expression of hepatitis B virus X and hepatitis C virus core protein in liver
- Authors
- 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.
- ID
- ZDB-PUB-120705-1
- Date
- 2012
- Source
- Hepatology (Baltimore, Md.) 56(6): 2268-2276 (Journal)
- Registered Authors
- Kawakami, Koichi
- Keywords
- fibrosis, TGF-β1, Tol2 transposon, liver-specific, Tet-Off
- MeSH Terms
-
- Smad2 Protein/genetics
- Cholangiocarcinoma/genetics*
- Cholangiocarcinoma/pathology
- Trans-Activators/genetics*
- Gene Expression/drug effects
- Cyclin D1/genetics
- Zebrafish*
- Up-Regulation
- Zebrafish Proteins/genetics
- Viral Core Proteins/genetics*
- p38 Mitogen-Activated Protein Kinases/genetics
- Bile Ducts, Intrahepatic*
- Vascular Endothelial Growth Factor A/genetics
- Anti-Bacterial Agents/pharmacology
- Disease Models, Animal*
- Doxycycline/pharmacology
- Mitogen-Activated Protein Kinase 3/genetics
- Animals
- Smad3 Protein/genetics
- Hepacivirus*
- Bile Duct Neoplasms/genetics*
- Bile Duct Neoplasms/pathology
- Connective Tissue Growth Factor/genetics
- MAP Kinase Signaling System
- Animals, Genetically Modified
- Transforming Growth Factor beta1/genetics
- PubMed
- 22729936 Full text @ Hepatology
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 co-expressed 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.