Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice.
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.
Rankin
Erinn B
EB
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6144, USA.
Rha
Jennifer
J
Unger
Travis L
TL
Wu
Chia H
CH
Shutt
Heather P
HP
Johnson
Randall S
RS
Simon
M Celeste
MC
Keith
Brian
B
Haase
Volker H
VH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006391:Hemangioma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D019426:Integrases / Q000378:metabolism; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*; D006623:von Hippel-Lindau Disease; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019426:Integrases; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse; C045073:Cre recombinase; C494469:VHL protein, mouse