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Flcn-deficient renal cells are tumorigenic and sensitive to mTOR suppression

Mingsong Wu1, Shuhui Si2, Yan Li3

  • 1Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi 563099, China.

Oncotarget
|September 30, 2015
PubMed

Insights

FLCN deficiency causes kidney tumors by activating the mTOR pathway. mTOR inhibitors like sirolimus show promise in treating FLCN-deficient renal cell carcinoma (RCC), particularly in Birt-Hogg-Dubé syndrome.

Area of Science:

  • Oncology
  • Molecular Biology
  • Nephrology

Background:

  • FLCN (Folliculin) deficiency activates the mTOR pathway in Birt-Hogg-Dubé syndrome-associated renal cell carcinoma (RCC).
  • A specific mouse model (Flcnflox/flox/Ksp-Cre) with kidney-specific Flcn deletion exhibits early mortality due to polycystic kidney disease.
  • The tumorigenic potential of Flcn-deficient kidney cells and the role of mTOR in this process remain unclear.

Purpose of the Study:

  • To investigate the tumorigenic potential of Flcn-deficient mouse kidney distal tubule cells.
  • To confirm the role of the mTOR pathway in the growth of Flcn-deficient tumors.
  • To evaluate the efficacy of mTOR inhibitors in controlling FLCN-deficient RCC.

Main Methods:

  • Generation of a kidney distal tubule-specific Flcn knockout (KO) mouse model.
  • Development and characterization of allograft tumors from Flcn-deficient mouse kidney cells.
  • Treatment of Flcn-deficient allograft and UOK 257-1 xenograft tumors with the mTOR inhibitor sirolimus.

Main Results:

  • Genetic disruption of Flcn in mouse kidney distal tubule cells induced tumorigenic transformation.
  • Flcn-deficient allograft tumors exhibited an aggressive histologic phenotype.
  • Sirolimus treatment significantly suppressed the growth of both Flcn-deficient allograft and human xenograft tumors, confirming mTOR pathway involvement.

Conclusions:

  • FLCN deficiency in mouse kidney distal tubule cells leads to aggressive, tumorigenic transformation.
  • The mTOR signaling pathway is crucial for the growth of FLCN-deficient renal tumors.
  • mTOR inhibitors represent a potential therapeutic strategy for FLCN-deficient RCC, including BHD-associated renal tumorigenesis.
Keywords:
BHDRCCkidney cancermTORsirolimus

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