HIF2α cooperates with RAS to promote lung tumorigenesis in mice

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Abstract

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 HIF2α 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 HIF2α is causal in imparting this poor prognosis is unknown. Here, we generated mice that conditionally express both a nondegradable variant of HIF2α 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 HIF2α causally in the pathogenesis of lung cancer in mice, demonstrate in vivo that HIF2α can promote expression of markers of EMT, and define HIF2α 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 HIF2α and prognosis in patients with NSCLC.

Authors

William Y. Kim, Samanthi Perera, Bing Zhou, Julian Carretero, Jen Jen Yeh, Samuel A. Heathcote, Autumn L. Jackson, Petros Nikolinakos, Beatriz Ospina, George Naumov, Kathleyn A. Brandstetter, Victor J. Weigman, Sara Zaghlul, D. Neil Hayes, Robert F. Padera, John V. Heymach, Andrew L. Kung, Norman E. Sharpless, William G. Kaelin Jr., Kwok-Kin Wong