Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice.

Rankin EB, Rha J, Unger TL, Wu CH, Shutt HP, Johnson RS, Simon MC, Keith B, Haase VH
Oncogene. 2008 27 (40): 5354-8

PMID: 18490920 · PMCID: PMC2575082 · DOI:10.1038/onc.2008.160

The von Hippel-Lindau tumor suppressor pVHL regulates the stability of hypoxia-inducible factors (HIF)-1 and -2, oxygen-sensitive basic helix-loop-helix transcription factors, which mediate the hypoxic induction of angiogenic growth factors such as vascular endothelial growth factor. Loss of pVHL function results in constitutive activation of HIF-1 and HIF-2 and is associated with the development of highly vascularized tumors in multiple organs. We have used a conditional gene-targeting approach to investigate the relative contributions of HIF-1 and HIF-2 to VHL-associated vascular tumorigenesis in a mouse model of liver hemangiomas. Here we demonstrate genetically that conditional inactivation of HIF-2alpha suppressed the development of VHL-associated liver hemangiomas and that angiogenic gene expression in hepatocytes is predominantly regulated by HIF-2 and not by HIF-1. These findings suggest that HIF-2 is the dominant HIF in the pathogenesis of VHL-associated vascular tumors and that pharmacologic targeting of HIF-2 may be an effective strategy for their treatment.

MeSH Terms (21)

Animals Basic Helix-Loop-Helix Transcription Factors Biomarkers, Tumor Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Hemangioma Hepatocytes Humans Hypoxia-Inducible Factor 1, alpha Subunit Integrases Liver Neoplasms Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Neovascularization, Pathologic Oligonucleotide Array Sequence Analysis Vascular Endothelial Growth Factor A von Hippel-Lindau Disease Von Hippel-Lindau Tumor Suppressor Protein

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