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

• Published in: Cancer cell 2008-12, Vol.14 (6), p.435-446
• Main Authors: Gordan, John D., Lal, Priti, Dondeti, Vijay R., Letrero, Richard, Parekh, Krishna N., Oquendo, C. Elisa, Greenberg, Roger A., Flaherty, Keith T., Rathmell, W. Kimryn, Keith, Brian, Simon, M. Celeste, Nathanson, Katherine L.
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - metabolism; Carcinoma, Renal Cell - diagnosis; Carcinoma, Renal Cell - metabolism; Cell Cycle; Cell Proliferation; CELLCYCLE; Disease Progression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kidney Neoplasms - diagnosis; Kidney Neoplasms - metabolism; Medical Oncology - methods; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction; Transcriptional Activation; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2008.10.016

von Hippel-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.