Hepatitis B Virus preS2 Domain Promotes Angiogenesis in Hepatocellular Carcinoma via Transcriptional Activation of VEGFA Promoter

Angiogenesis is closely related to the development and progression of hepatocellular carcinoma (HCC). Angiogenic factors have been confirmed to be overexpressed in HCC. The hepatitis B virus preS2 domain is a transactivator that plays an important role in hepatitis B virus (HBV)-related HCC. Here, we aimed to investigate the potential of the preS2 domain in inducing angiogenesis in HCC. A total of 25 cases of pathologically confirmed HCC were screened. The levels of preS2, CD34, and vascular endothelial growth factor A (VEGFA) in HCC samples were evaluated by immunohistochemistry (IHC). The proliferation of vascular endothelial cells was detected by CCK-8. Besides, VEGFA was analyzed by Western blot in HCC cells. The effect of preS2 on the VEGFA promoter was measured by dual-luciferase reporter assays. We found that preS2 domain-positive HCCs had significantly higher microvessel density (MVD) and VEGFA expression than preS2 domain-negative HCCs. Overexpression of preS2 upregulated VEGFA expression in HepG2 and activated vascular endothelial cell proliferation. However, blocking preS2 expression reduced VEGFA expression in HepG2.2.15 and inhibited the proliferation of vascular endothelial cells. In addition, a dual-luciferase assay indicated that the preS2 domain could activate VEGFA promoter activity. In conclusion, we showed that the expression of the preS2 domain promotes angiogenesis by transactivating the VEGFA promoter in HCC.