title: HIF2alpha cooperates with RAS to promote   lung tumorigenesis in mice.
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 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.
authors: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA. wykim@med.unc.edu
authors: William Y
authors: WY
authors: Kim
authors: Samanthi
authors: S
authors: Perera
authors: Bing
authors: B
authors: Zhou
authors: Julian
authors: J
authors: Carretero
authors: Jen Jen
authors: JJ
authors: Yeh
authors: Samuel A
authors: SA
authors: Heathcote
authors: Autumn L
authors: AL
authors: Jackson
authors: Petros
authors: P
authors: Nikolinakos
authors: Beatriz
authors: B
authors: Ospina
authors: George
authors: G
authors: Naumov
authors: Kathleyn A
authors: KA
authors: Brandstetter
authors: Victor J
authors: VJ
authors: Weigman
authors: Sara
authors: S
authors: Zaghlul
authors: D Neil
authors: DN
authors: Hayes
authors: Robert F
authors: RF
authors: Padera
authors: John V
authors: JV
authors: Heymach
authors: Andrew L
authors: AL
authors: Kung
authors: Norman E
authors: NE
authors: Sharpless
authors: William G
authors: WG
authors: Kaelin
authors: Kwok-Kin
authors: KK
authors: Wong
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002454:Cell Differentiation; D004727:Endothelium / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D027701:Organic Cation Transport Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099254:Organic Cation Transporter 3
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D027701:Organic Cation Transport Proteins; D016283:Proto-Oncogene Proteins p21(ras); D000099162:Endothelial PAS Domain-Containing Protein 1; D000099254:Organic Cation Transporter 3; C495971:Hras protein, mouse