HIF-alpha 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-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.
Gordan
John D
JD
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Lal
Priti
P
Dondeti
Vijay R
VR
Letrero
Richard
R
Parekh
Krishna N
KN
Oquendo
C Elisa
CE
Greenberg
Roger A
RA
Flaherty
Keith T
KT
Rathmell
W Kimryn
WK
Keith
Brian
B
Simon
M Celeste
MC
Nathanson
Katherine L
KL
D000951:Antigens, Neoplasm / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D008495:Medical Oncology / Q000379:methods; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D000951:Antigens, Neoplasm; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016271:Proto-Oncogene Proteins c-myc; D051794:Von Hippel-Lindau Tumor Suppressor Protein