期刊
CANCER CELL
卷 14, 期 6, 页码 435-446出版社
CELL PRESS
DOI: 10.1016/j.ccr.2008.10.016
关键词
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资金
- NIH [CA104838, R01 CA01 121781]
- Hughes Medical Institute
- DiBona Foundation
- NIH Medical Scientist Training Grant
- NRSA [T32]
- V Foundation
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-1 alpha and HIF-2 alpha 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-1 alpha/HIF-2 alpha-expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling. In contrast, pVHL-deficient ccRCCs expressing only HIF-2 alpha 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.
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