FoxOs 建立一个进展检查点来限制 mTORC1 激活的肾肿瘤发生。
FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis.
机构信息
Belfer Institute for Applied Cancer Science, Boston, MA 02115, USA.
出版信息
Cancer Cell. 2010 Nov 16;18(5):472-84. doi: 10.1016/j.ccr.2010.10.019.
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.
mTORC1 是肾细胞癌 (RCC) 的一个经过验证的治疗靶点。在这里，对 Tsc1 缺陷型（mTORC1 过度激活）小鼠的分析揭示了一个 FoxO 依赖性的负反馈回路，限制了 mTORC1 介导的肾肿瘤发生。我们记录了 Tsc1 缺陷型良性多囊肾中 FoxO 的强烈激活，以及向小鼠肾肿瘤进展时 FoxO 的消失；在 Tsc1 和 FoxOs 双基因缺失的小鼠中，肾肿瘤进展；以及在大多数人类肾透明细胞癌和乳头状癌中 FoxO 表达下调，但在侵袭性较低的 RCC 和良性肾肿瘤亚型中仍持续表达。通过整合分析，我们揭示了 FoxO 介导的阻滞作用是通过上调 Myc 拮抗剂 Mxi1-SRα 和 mir-145 来抑制 Myc 而发挥作用的，从而建立了 FoxO-Mxi1-SRα/mir-145 轴作为肾肿瘤发展的主要进展阻滞。
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