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

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 anal...

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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
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Summary: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.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2008.10.016