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PMID: 19061835 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cancer cell ·Vol. 14 ·No. 6 ·2008-12-09 ·Pages 435-46

Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, Greenberg RA, Flaherty KT, Rathmell WK, Keith B, Simon MC, Nathanson KL

Abstract

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
Antigens, Neoplasm/metabolism Carcinoma, Renal Cell/diagnosis,metabolism Cell Cycle Cell Proliferation Disease Progression Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Kidney Neoplasms/diagnosis,metabolism Medical Oncology/methods Proto-Oncogene Proteins c-myc/metabolism Signal Transduction Transcriptional Activation Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Chemicals
Antigens, Neoplasm Hypoxia-Inducible Factor 1, alpha Subunit Proto-Oncogene Proteins c-myc Von Hippel-Lindau Tumor Suppressor Protein
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Gordan John D
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2008.10.016
Published
2008-12-09
Pages
435-46
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2621440
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NCI NIH HHS · CA104838 · United States
NCI NIH HHS · P01 CA104838-040002 · United States
NCI NIH HHS · R01 CA121781-04 · United States
NCI NIH HHS · R01 CA01121781 · United States
NCI NIH HHS · P01 CA104838 · United States
NCI NIH HHS · R01 CA121781 · United States
Databases
GEO
GSE11904, GSE11985, GSE13282
Corrections
CommentIn
PMID: 19061830
External Links
PubMed source DOI: 10.1016/j.ccr.2008.10.016 PMC Full Text View journal details
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