Author/Authors :
Gordan، نويسنده , , John D. and Lal، نويسنده , , Priti and Dondeti، نويسنده , , Vijay R. and Letrero، نويسنده , , Richard and Parekh، نويسنده , , Krishna N. and Oquendo، نويسنده , , C. Elisa and Greenberg، نويسنده , , Roger A. and Flaherty، نويسنده , , Keith T. and Rathmell، نويسنده , , W. Kimryn and Keith، نويسنده , , Brian and Simon، نويسنده , , M. Celeste and Nathanson، نويسنده , , Katherine L.، نويسنده ,
Abstract :
Summary
ppel-Lindau (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.
