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Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice

Abstract

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-2α 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.

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Acknowledgements

This work was supported by NIH grant DK073467 and CA100787 (both to VHH), the Center for Molecular Studies in Digestive and Liver Disease (P30-DK50306) and the Penn Diabetes and Endocrinology Research Center Functional Genomics Core (P30-DK19525). EBR was supported by a fellowship grant from the American Heart Association.

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Correspondence to V H Haase.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Rankin, E., Rha, J., Unger, T. et al. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene 27, 5354–5358 (2008). https://doi.org/10.1038/onc.2008.160

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