HIF2alpha cooperates with RAS to promote   lung tumorigenesis in mice.
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.
Kim
William Y
WY
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA. wykim@med.unc.edu
Perera
Samanthi
S
Zhou
Bing
B
Carretero
Julian
J
Yeh
Jen Jen
JJ
Heathcote
Samuel A
SA
Jackson
Autumn L
AL
Nikolinakos
Petros
P
Ospina
Beatriz
B
Naumov
George
G
Brandstetter
Kathleyn A
KA
Weigman
Victor J
VJ
Zaghlul
Sara
S
Hayes
D Neil
DN
Padera
Robert F
RF
Heymach
John V
JV
Kung
Andrew L
AL
Sharpless
Norman E
NE
Kaelin
William G
WG
Wong
Kwok-Kin
KK
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
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