FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal Tumorigenesis

被引：131

作者：

Gan, Boyi ^{[1
,2
,3
,4
]}

Lim, Carol ^{[1
,2
,3
,4
]}

Chu, Gerald ^{[1
,3
,4
,5
]}

Hua, Sujun ^{[1
,2
,3
,4
]}

Ding, Zhihu ^{[1
,2
,3
,4
]}

Collins, Michael ^{[5
]}

Hu, Jian ^{[1
,2
,3
,4
]}

Jiang, Shan ^{[1
,2
,3
,4
]}

Fletcher-Sananikone, Eliot ^{[1
,2
,3
,4
]}

Zhuang, Li ^{[1
,2
,3
,4
]}

Chang, Michelle ^{[5
]}

Zheng, Hongwu ^{[1
,2
,3
,4
]}

Wang, Y. Alan ^{[1
,2
,3
,4
]}

Kwiatkowski, David J. ^{[6
]}

Kaelin, William G., Jr. ^{[2
,3
,7
]}

Signoretti, Sabina ^{[2
,5
]}

DePinho, Ronald A. ^{[1
,2
,3
,4
]}

机构：

[1] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Div Translat Med, Boston, MA 02115 USA

[7] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

CANCER CELL | 2010年 / 18卷 / 05期

关键词：

C-MYC; CELL CARCINOMA; MTOR PATHWAY; HISTONE DEACETYLASE; N-COR; COMPLEX; METABOLISM; REPRESSION; INDUCTION; CANCER;

D O I：

10.1016/j.ccr.2010.10.019

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 Fox Os; 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-SR alpha and mir-145, establishing a FoxO-Mxi1-SR alpha/mir-145 axis as a major progression block in renal tumor development.

引用

页码：472 / 484

页数：13

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