Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1alpha.

Hepatitis B virus X protein (HBx) is closely involved in the development of hepatocellular carcinoma, a highly vascularized solid tumor. Here we show that HBx increases the transcriptional activity and protein level of hypoxia-inducible factor-1alpha (HIF-1alpha) under both normoxic and hypoxic conditions, and it also stimulates angiogenesis. HBx directly interacted with the bHLH/PAS domain of HIF-1alpha but not with the von Hippel-Lindau protein (pVHL). HBx decreased the binding of pVHL to HIF-1alpha and prevented ubiquitin-dependent degradation of HIF-1alpha. In HBx-transgenic mice, HIF-1alpha and vascular endothelial growth factor were strongly detected in the dysplastic lesion, where HBx was also more highly expressed than in the non-neoplastic region of the liver. An immunohistochemical study showed that microvessels are more abundant in the dysplastic lesion than in the non-neoplastic region. Our data suggest that HBx stabilizes HIF-1alpha and leads to angiogenesis during hepatocarcinogenesis.