HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice

J Clin Invest. 2009 Aug;119(8):2160-70. doi: 10.1172/jci38443.


Members of the hypoxia-inducible factor (HIF) family of transcription factors regulate the cellular response to hypoxia. In non-small cell lung cancer (NSCLC), high HIF2alpha levels correlate with decreased overall survival, and inhibition of either the protein encoded by the canonical HIF target gene VEGF or VEGFR2 improves clinical outcomes. However, whether HIF2alpha is causal in imparting this poor prognosis is unknown. Here, we generated mice that conditionally express both a nondegradable variant of HIF2alpha and a mutant form of Kras (KrasG12D) that induces lung tumors. Mice expressing both Hif2a and KrasG12D in the lungs developed larger tumors and had an increased tumor burden and decreased survival compared with mice expressing only KrasG12D. Additionally, tumors expressing both KrasG12D and Hif2a were more invasive, demonstrated features of epithelial- mesenchymal transition (EMT), and exhibited increased angiogenesis associated with mobilization of circulating endothelial progenitor cells. These results implicate HIF2alpha causally in the pathogenesis of lung cancer in mice, demonstrate in vivo that HIF2alpha can promote expression of markers of EMT, and define HIF2alpha as a promoter of tumor growth and progression in a solid tumor other than renal cell carcinoma. They further suggest a possible causal relationship between HIF2alpha and prognosis in patients with NSCLC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Cell Differentiation
  • Endothelium / pathology
  • Gene Expression Profiling
  • Humans
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Mesoderm / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness
  • Organic Cation Transport Proteins / genetics
  • Proto-Oncogene Proteins p21(ras) / physiology*


  • Basic Helix-Loop-Helix Transcription Factors
  • Organic Cation Transport Proteins
  • solute carrier family 22 (organic cation transporter), member 3
  • endothelial PAS domain-containing protein 1
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)