HIF-α Effects on c-Myc Distinguish Two Subtypes of Sporadic VHL-Deficient Clear Cell Renal Carcinoma

摘要: von Hippel-Lindau (VHL) tumor suppressor loss results in hypoxia-inducible factor alpha (HIF-alpha) stabilization and occurs 70% of sporadic clear cell renal carcinomas (ccRCCs). To determine whether opposing influences HIF-1alpha HIF-2alpha on c-Myc activity regulate human ccRCC progression, we analyzed VHL genotype HIF-alpha expression 160 primary tumors, which segregated into three groups with distinct molecular characteristics. Interestingly, ccRCCs intact VHL, as well pVHL-deficient HIF-1alpha/HIF-2alpha-expressing ccRCCs, exhibited enhanced Akt/mTOR ERK/MAPK signaling. In contrast, expressing only displayed elevated activity, resulting proliferation resistance to replication stress. These reproducible distinctions behavior delineate effects vivo suggest criteria for selecting targeted therapies.