Transgenic HBV X and HCV Core co-expression Leads to Liver Inflammation and Fibrosis in Zebrafish
Date Issued
2009
Date
2009
Author(s)
Chen, Yi-Meng
Abstract
Epidemically, co-infection with hepatitis B and C can significantly increase the risk of development of fulminant hepatitis, cirrhosis and hepatocelluar carcinoma(HCC). HBV x (HBx) and HCV core proteins (HCP) are associated with liver cirrhosis and represent major risk factors for HCC development. We aim to establish liver-specific HBx and HCP double transgenic zebrafish to study the dual infection pathogenesis and molecular mechanism in tumor formation. Here, we use tetracycline inducible expression system (tetracycline-off system) which can conditionally express transgenes, involving two vectors: one contains tTA(trans-tetracycline activator) driven by liver specific L-FABP (liver-type fatty acid binding protein) promoter, another with TRE(tetracycline responding element) site flanked by bidirectional CMV promoter to simultaneously express transgenes and reporter genes, such as GFP. Combining with Tol2 transposon system can increase efficiency of transgensis. Histological evidences shows about 30% pathological occurrence (20% inflammation and 10% fibrosis) in 1.5-month-old double transgenic fish, and the fibrosis ratio has been increased in 3–month-old adult fish about 30%. Even found malignancy tumour formation in severe fibrosis fish. However, compared to the control、no significant pathological change was observed in single transgenic zebrafish. Further, we performed quantitative RT-PCR to analysis fibrosis-related genes. Results showed that several inflammation and cell necrosis marker genes (TGF-β、TNFα、NFκB、Cox2a) were highly expressed, and the expression level of CTGF, a mediator of the profibrotic activities of TGFβ1 (a known regulator of fibrosis) is correlated with the degree of fibrosis phenotype, regulate by HCP and HBx. These findings might suggest that connective tissue growth factor (CTGF) play an important role in co-expression inducing liver fibrosis mechanism. In conclusion, this is the first liver tumorigenesis animal model with hepatitis B and C viral proteins co-expression. Perspectively, this model can provide a good material for investigating the cross-talk between HCP and HBx.
Subjects
CTGF
fibrosis
hepatitis virus
transgenesis
zebrafish
SDGs
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