Journal of biomedical science · 2020
Statin inhibits large hepatitis delta antigen-Smad3 -twist-mediated epithelial-to-mesenchymal transition and hepatitis D virus secretion.
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Liang Yuh-Jin, Sun Cheng-Pu, Hsu Yu-Chen, Chen Yi-Wen, Wang I-An, Su Chien-Wei, Tao Mi-Hua, Wu Jaw-Ching
Аннотация
BACKGROUND: Hepatitis D virus (HDV) infection may induce fulminant hepatitis in chronic hepatitis B patients (CHB) or rapid progression of CHB to cirrhosis or hepatocellular carcinoma. There is no effective treatment for HDV infection. HDV encodes small delta antigens (S-HDAg) and large delta antigens (L-HDAg). S-HDAg is essential for HDV replication. Prenylated L-HDAg plays a key role in HDV assembly. Previous studies indicate that L-HDAg transactivates transforming growth factor beta (TGF-β) and induces epithelial-mesenchymal transition (EMT), possibly leading to liver fibrosis. However, the mechanism is unclear.
METHODS: The mechanisms of the activation of Twist promoter by L-HDAg were investigated by luciferase reporter assay, chromatin immunoprecipitation, and co-immunoprecipitation analysis. ELISA and Western blotting were used to analyze L-HDAg prenylation, TGF-β secretion, expression of EMT markers, and to evaluate efficacy of statins for HDV treatment.
RESULTS: We found that L-HDAg activated Twist expression, TGF-β expression and consequently induced EMT, based on its interaction with Smad3 on Twist promoter. The treatment of statin, a prenylation inhibitor, resulted in reduction of Twist promoter activity, TGF-β expression, and EMT, and reduces the release of HDV virions into the culture medium.
CONCLUSIONS: We demonstrate that L-HDAg activates EMT via Twist and TGF-β activation. Treatment with statins suppressed Twist expression, and TGF-β secretion, leading to downregulation of EMT. Our findings clarify the mechanism of HDV-induced EMT, and provide a basis for possible novel therapeutic strategies against HDV infection.
METHODS: The mechanisms of the activation of Twist promoter by L-HDAg were investigated by luciferase reporter assay, chromatin immunoprecipitation, and co-immunoprecipitation analysis. ELISA and Western blotting were used to analyze L-HDAg prenylation, TGF-β secretion, expression of EMT markers, and to evaluate efficacy of statins for HDV treatment.
RESULTS: We found that L-HDAg activated Twist expression, TGF-β expression and consequently induced EMT, based on its interaction with Smad3 on Twist promoter. The treatment of statin, a prenylation inhibitor, resulted in reduction of Twist promoter activity, TGF-β expression, and EMT, and reduces the release of HDV virions into the culture medium.
CONCLUSIONS: We demonstrate that L-HDAg activates EMT via Twist and TGF-β activation. Treatment with statins suppressed Twist expression, and TGF-β secretion, leading to downregulation of EMT. Our findings clarify the mechanism of HDV-induced EMT, and provide a basis for possible novel therapeutic strategies against HDV infection.