- 作者: Yuh-Jin Liang, Cheng-Pu Sun, Yu-Chen Hsu, Yi-Wen Chen, I-An Wang, Chien-Wei Su, Mi-Hua Tao and Jaw-Ching Wu
- 作者服務機構: 1. Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan, Republic of China 2. Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 115, Taiwan, Republic of China 3. Institute of Clinical Medicine, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan, Republic of China 4. Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan, Republic of China 5. Faculty of Medicine, School of Medicine, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan, Republic of China 6. Cancer Progression Research Center, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan, Republic of China
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: Prenylation inhibitors, Statins, Hepatitis delta antigens, Smad3, Twist promoter, Epithelial-mesenchymal transition