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[Cancer Research 66, 6264-6270, June 15, 2006]
© 2006 American Association for Cancer Research

Cell, Tumor, and Stem Cell Biology

Role of Hypoxia-Inducible Factor (HIF)-1{alpha} versus HIF-2{alpha} in the Regulation of HIF Target Genes in Response to Hypoxia, Insulin-Like Growth Factor-I, or Loss of von Hippel-Lindau Function: Implications for Targeting the HIF Pathway

Veronica A. Carroll and Margaret Ashcroft

Cell Growth Regulation and Angiogenesis Laboratory, Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, United Kingdom

Requests for reprints: Margaret Ashcroft, Cell Growth Regulation and Angiogenesis Laboratory, Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44-208-7224035; Fax: 44-208-7224205; E-mail: margaret.ashcroft{at}icr.ac.uk.

Overexpression of hypoxia-inducible factors (HIF), HIF-1{alpha} and HIF-2{alpha}, leads to the up-regulation of genes involved in proliferation, angiogenesis, and glucose metabolism and is associated with tumor progression in several cancers. However, the contribution of HIF-1{alpha} versus HIF-2{alpha} to vascular endothelial growth factor (VEGF) expression and other HIF-regulated target genes under different conditions is unclear. To address this, we used small interfering RNA (siRNA) techniques to knockdown HIF-1{alpha} and/or HIF-2{alpha} expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1{alpha} and/or HIF-2{alpha} due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1{alpha} primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2{alpha} in MCF-7 cells. We also observed a reciprocal relationship between HIF-1{alpha} and HIF-2{alpha} expression in hypoxia in these cells: HIF-2{alpha} siRNA enhanced HIF-1{alpha}–mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1{alpha} siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1{alpha} and HIF-2{alpha} due to loss of VHL function, we found that high basal VEGF, glucose transporter-1, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 expression was predominantly dependent on HIF-2{alpha}. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2{alpha} protein expression and HIF-2{alpha}–regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically. (Cancer Res 2006; 66(12): 6264-70)




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