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. Hepatocarcinogenesis generally included an active angiogenesis that was mainly considered to be due to a local hypoxia in liver tissues. However, the exact mechanisms of HBx-induced hepatocarcinogenesis were poorly understood. In this study, we examined the role of HBx in the increased angiogenesis and the possible regulating mechanisms of HBx by hypoxia. We demonstrated that HBx stimulated the transcription of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in HBx-stable transfectants. HBx-induced angiogenesis was confirmed by in vivo tumor angiogenesis assay, resulting in that the HBx transfectants increased the formation of new blood vessels compared to the control transfectants. Then, we demonstrated that the expression of HBx was enhanced after incubating HBV-infected hepatoma cells under hypoxia. Moreover, 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 critical role in the hypoxia-induced angiogenesis through transcriptional activation of VEGF during hepatocarcinogenesis.
Lee
S W
SW
Department of Molecular Biology, Pusan National University, Pusan, 609-735, Korea.
Lee
Y M
YM
Bae
S K
SK
Murakami
S
S
Yun
Y
Y
Kim
K W
KW
D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000821:virology; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000821:virology*; D010100:Oxygen / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D054334:Viral Regulatory and Accessory Proteins
D016228:Endothelial Growth Factors; D008222:Lymphokines; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D010100:Oxygen