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Cancer Cell. 2010 Nov 16;18(5):472-84. doi: 10.1016/j.ccr.2010.10.019.

FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis.

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1
Belfer Institute for Applied Cancer Science, Boston, MA 02115, USA.

Abstract

mTORC1 is a validated therapeutic target for renal cell carcinoma (RCC). Here, analysis of Tsc1-deficient (mTORC1 hyperactivation) mice uncovered a FoxO-dependent negative feedback circuit constraining mTORC1-mediated renal tumorigenesis. We document robust FoxO activation in Tsc1-deficient benign polycystic kidneys and FoxO extinction on progression to murine renal tumors; murine renal tumor progression on genetic deletion of both Tsc1 and FoxOs; and downregulated FoxO expression in most human renal clear cell and papillary carcinomas, yet continued expression in less aggressive RCCs and benign renal tumor subtypes. Mechanistically, integrated analyses revealed that FoxO-mediated block operates via suppression of Myc through upregulation of the Myc antagonists, Mxi1-SRα and mir-145, establishing a FoxO-Mxi1-SRα/mir-145 axis as a major progression block in renal tumor development.

PMID:
21075312
PMCID:
PMC3023886
DOI:
10.1016/j.ccr.2010.10.019
[Indexed for MEDLINE]
Free PMC Article

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