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

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.
Hepatology (Baltimore, Md.)   56(6): 2268-2276 (Journal)
Registered Authors
Kawakami, Koichi
fibrosis, TGF-β1, Tol2 transposon, liver-specific, Tet-Off
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Anti-Bacterial Agents/pharmacology
  • Bile Duct Neoplasms/genetics*
  • Bile Duct Neoplasms/pathology
  • Bile Ducts, Intrahepatic*
  • Cholangiocarcinoma/genetics*
  • Cholangiocarcinoma/pathology
  • Connective Tissue Growth Factor/genetics
  • Cyclin D1/genetics
  • Disease Models, Animal*
  • Doxycycline/pharmacology
  • Gene Expression/drug effects
  • Hepacivirus*
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase 3/genetics
  • Smad2 Protein/genetics
  • Smad3 Protein/genetics
  • Trans-Activators/genetics*
  • Transforming Growth Factor beta1/genetics
  • Up-Regulation
  • Vascular Endothelial Growth Factor A/genetics
  • Viral Core Proteins/genetics*
  • Zebrafish*
  • Zebrafish Proteins/genetics
  • p38 Mitogen-Activated Protein Kinases/genetics
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.

Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes