Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis

The hepatitis B virus (HBV)-encoded transcriptional activator HBV-X protein (HBx) was known to be involved in hepatocarcinogenesis. Hepatocarcinogenes is generally included an active angiogenesis that was mainly considered to be due to a local hypoxia in liver tissues. However, the exact mechanisms o f HBx-induced hepatocarcinogenesis were poorly understood. In this study, w e examined the role of HBx in the increased angiogenesis and the possible r egulating mechanisms of HBx by hypoxia. We demonstrated that HBx stimulated the transcription of vascular endothelial growth factor (VEGF), a potent a ngiogenic factor, in HBx-stable transfectants, HBx-induced angiogenesis was confirmed by in vivo tumor angiogenesis assay, resulting in that the HBx t ransfectants increased the formation of new blood vessels compared to the c ontrol transfectants, Then, we demonstrated that the expression of HBx was enhanced after incubating HBV-infected hepatoma cells under hypoxia, Moreov er, the activity of HBV enhancer 1 (Enh1) was increased when hepatoma cells transfected with the reporter plasmid containing HBV Enh1 were exposed to hypoxic conditions. These results strongly suggest that HBx may play a crit ical role in the hypoxia-induced angiogenesis through transcriptional activ ation of VEGF during hepatocarcinogenesis. (C) 2000 Academic Press.