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Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha 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.
Cancer Res. 2006 Jun 15; 66(12):6264-70.CR

Abstract

Overexpression of hypoxia-inducible factors (HIF), HIF-1alpha and HIF-2alpha, 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-1alpha versus HIF-2alpha 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-1alpha and/or HIF-2alpha expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1alpha and/or HIF-2alpha due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1alpha primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2alpha in MCF-7 cells. We also observed a reciprocal relationship between HIF-1alpha and HIF-2alpha expression in hypoxia in these cells: HIF-2alpha siRNA enhanced HIF-1alpha-mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1alpha siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1alpha and HIF-2alpha 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-2alpha. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2alpha protein expression and HIF-2alpha-regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically.

Authors+Show Affiliations

Cell Growth Regulation and Angiogenesis Laboratory, Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, United Kingdom.No affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16778202

Citation

Carroll, Veronica A., and Margaret Ashcroft. "Role of Hypoxia-inducible Factor (HIF)-1alpha Versus HIF-2alpha 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." Cancer Research, vol. 66, no. 12, 2006, pp. 6264-70.
Carroll VA, Ashcroft M. Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha 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. Cancer Res. 2006;66(12):6264-70.
Carroll, V. A., & Ashcroft, M. (2006). Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha 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. Cancer Research, 66(12), 6264-70.
Carroll VA, Ashcroft M. Role of Hypoxia-inducible Factor (HIF)-1alpha Versus HIF-2alpha 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. Cancer Res. 2006 Jun 15;66(12):6264-70. PubMed PMID: 16778202.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha 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. AU - Carroll,Veronica A, AU - Ashcroft,Margaret, PY - 2006/6/17/pubmed PY - 2006/8/11/medline PY - 2006/6/17/entrez SP - 6264 EP - 70 JF - Cancer research JO - Cancer Res VL - 66 IS - 12 N2 - Overexpression of hypoxia-inducible factors (HIF), HIF-1alpha and HIF-2alpha, 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-1alpha versus HIF-2alpha 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-1alpha and/or HIF-2alpha expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1alpha and/or HIF-2alpha due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1alpha primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2alpha in MCF-7 cells. We also observed a reciprocal relationship between HIF-1alpha and HIF-2alpha expression in hypoxia in these cells: HIF-2alpha siRNA enhanced HIF-1alpha-mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1alpha siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1alpha and HIF-2alpha 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-2alpha. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2alpha protein expression and HIF-2alpha-regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/16778202/Role_of_hypoxia_inducible_factor__HIF__1alpha_versus_HIF_2alpha_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_ DB - PRIME DP - Unbound Medicine ER -