Abstract
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.
MeSH terms
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Animals
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Cell Line
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Humans
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Hypoxia / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit
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Mice
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Mice, Transgenic
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Models, Biological
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Neovascularization, Physiologic*
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Protein Binding
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Protein Processing, Post-Translational
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / metabolism
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Ubiquitin / antagonists & inhibitors
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / antagonists & inhibitors
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Ubiquitin-Protein Ligases / metabolism
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Vascular Endothelial Growth Factors / biosynthesis
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Vascular Endothelial Growth Factors / metabolism
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Viral Regulatory and Accessory Proteins
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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RNA, Messenger
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Trans-Activators
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Transcription Factors
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Tumor Suppressor Proteins
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Ubiquitin
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Vascular Endothelial Growth Factors
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Viral Regulatory and Accessory Proteins
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hepatitis B virus X protein
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human