HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma.

Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, Greenberg RA, Flaherty KT, Rathmell WK, Keith B, Simon MC, Nathanson KL
Cancer Cell. 2008 14 (6): 435-46

PMID: 19061835 · PMCID: PMC2621440 · DOI:10.1016/j.ccr.2008.10.016

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

MeSH Terms (15)

Antigens, Neoplasm Carcinoma, Renal Cell Cell Cycle Cell Proliferation Disease Progression Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Hypoxia-Inducible Factor 1, alpha Subunit Kidney Neoplasms Medical Oncology Proto-Oncogene Proteins c-myc Signal Transduction Transcriptional Activation Von Hippel-Lindau Tumor Suppressor Protein

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