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

Boyi Gan1, Carol Lim, Gerald Chu

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

Cancer Cell
|November 16, 2010
PubMed

Insights

A newly discovered FoxO-dependent circuit restrains kidney cancer growth by suppressing Myc. This pathway is lost in aggressive renal cell carcinoma (RCC), highlighting its potential as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mammalian target of rapamycin complex 1 (mTORC1) is a key driver of renal cell carcinoma (RCC) and a validated therapeutic target.
  • Understanding the regulatory mechanisms controlling renal tumorigenesis is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the role of the FoxO transcription factor in regulating mTORC1-driven renal tumorigenesis.
  • To elucidate the molecular mechanisms by which FoxO influences renal tumor progression.

Main Methods:

  • Analysis of Tsc1-deficient mice with hyperactivated mTORC1 to model renal tumorigenesis.
  • Genetic manipulation to assess the impact of FoxO deletion on tumor development.
  • Examination of FoxO expression in human RCC and benign renal tumor subtypes.
  • Integrated molecular analyses to identify downstream targets of FoxO.

Main Results:

  • FoxO is robustly activated in benign Tsc1-deficient kidneys but extinguished during progression to murine renal tumors.
  • Genetic deletion of FoxO accelerates tumor progression in Tsc1-deficient mice.
  • Downregulated FoxO expression is observed in most human clear cell and papillary RCCs, with sustained expression in less aggressive subtypes and benign tumors.
  • FoxO suppresses Myc oncogene expression by upregulating Myc antagonists Mxi1-SRα and mir-145.

Conclusions:

  • A FoxO-dependent negative feedback circuit, involving Mxi1-SRα and mir-145, acts as a critical suppressor of mTORC1-mediated renal tumorigenesis.
  • Loss of this FoxO-mediated suppression is a key event in the progression of renal tumors.
  • The FoxO-Mxi1-SRα/mir-145 axis represents a potential therapeutic strategy for inhibiting renal tumor development.

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