Summary VHL tumor suppressor loss results in hypoxia inducible factor-alpha (HIF-α) stabilization, and occurs in 70% of sporadic clear cell renal carcinomas (ccRCCs). To determine whether opposing influences of HIF-1α and HIF-2α on c-Myc activity regulate human ccRCC progression, we analyzed VHL genotype and HIF-α expression in 160 primary tumors, which segregated into three groups with distinct molecular characteristics. Interestingly, ccRCCs with intact VHL, as well as pVHL-deficient, HIF-1α/HIF-2α expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling. In contrast, pVHL-deficient ccRCCs expressing only HIF-2α displayed elevated c-Myc activity, resulting in enhanced proliferation and resistance to replication stress. These reproducible distinctions in ccRCC behavior delineate HIF-α effects on c-Myc in vivo and suggest molecular criteria for selecting targeted therapies. Significance Constitutive HIF activity is clearly associated with ccRCC tumorigenesis; however, the influence of individual HIF-α subunits on cell growth mechanisms in vivo is unknown. Few dominant oncogenic pathways have been identified within ccRCC, making it difficult to select optimal targeted therapies for patients, or to predict disease outcome, except by grade and stage. Cell culture experiments indicate that HIF-1α inhibits the c-Myc oncoprotein, whereas HIF-2α potentiates c-Myc transcriptional activity and cellular proliferation. The findings reported here indicate that HIF-1α and HIF-2α promote distinct oncogene activation in human ccRCCs, and reveal a critical role for HIF-2α and c-Myc in promoting genomic integrity. These results suggest that evaluating pVHL status and HIF-α expression may aid targeted therapy selection for human ccRCCs.

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