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Renal tumour suppressor function of the Birt–Hogg–Dubé syndrome gene product folliculin
  1. V Hudon1,
  2. S Sabourin1,
  3. A B Dydensborg1,
  4. V Kottis1,
  5. A Ghazi1,
  6. M Paquet2,
  7. K Crosby3,
  8. V Pomerleau1,
  9. N Uetani1,
  10. A Pause1
  1. 1Goodman Cancer Centre and Department of Biochemistry, McGill University, Montréal, Québec, Canada
  2. 2Comparative Medicine and Animal Resources Centre, McGill University, Montreal, Quebec, Canada
  3. 3Cell Signaling Technologies, Danvers, Massachusetts, USA
  1. Correspondence to Arnim Pause, Goodman Cancer Centre, McGill University, Room 707A, McIntyre Building, 3655 Sir William Osler Promenade, Montréal, Québec, Canada H3G1Y6; arnim.pause{at}


Background Renal cell carcinoma (RCC) comprises five major molecular and histological subtypes. The Birt–Hogg–Dubé (BHD) syndrome is a hereditary human cancer syndrome that predisposes affected individuals to develop renal carcinoma of nearly all subtypes, in addition to benign fibrofolliculomas, and pulmonary and renal cysts. BHD is caused by loss-of-function mutations in the folliculin (FLCN) protein. The molecular function of FLCN is still largely unknown; opposite and conflicting evidence of the role of FLCN in mammalian target of rapamycin signalling/phosphorylated ribosomal protein S6 (p-S6) activation had recently been reported.

Results and Methods Here, the expression pattern of murine Flcn was described, and it was observed that homozygous disruption of Flcn results in embryonic lethality early during development. Importantly, heterozygous animals manifest early preneoplastic kidney lesions, devoid of Flcn expression, that progress towards malignancy, including cystopapillary adenomas. A bona fide tumour suppressor activity of FLCN was confirmed by nude mouse xenograft assays of two human RCC cell lines with either diminished or re-expressed FLCN. It was observed that loss of FLCN expression leads to context-dependent effects on S6 activation. Indeed, solid tumours and normal kidneys show decreased p-S6 upon diminished FLCN expression. Conversely, p-S6 is found to be elevated or absent in FLCN-negative renal cysts.

Conclusion In accordance with clinical data showing distinct renal malignancies arising in BHD patients, in this study FLCN is shown as a general tumour suppressor in the kidney.

  • BHD syndrome
  • kidney cysts
  • renal adenocarcinoma
  • folliculin
  • mTORC1
  • molecular genetics
  • oncology
  • cancer: urological
  • cell biology
  • renal medicine
  • BHD
  • Birt–Hogg–Dubé
  • β-geo
  • β-galactosidase-neomycin-phosphotransferase II
  • E
  • embryonic day
  • FLCN
  • folliculin
  • LOH
  • loss of heterozygosity
  • mTOR
  • mammalian target of rapamycin
  • RCC
  • renal cell carcinoma
  • RCND
  • renal cysadenocarcinoma and nodular dermatofibrosis
  • SEM
  • standard error of the mean
  • TSC
  • tuberous sclerosis complex
  • VHL
  • von Hippel Lindau

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  • SS, ABD and VK are equal contributors.

  • Funding This work was supported by grant from the Kidney Foundation of Canada and a Miriam and Saul Goldberg internal Goodman Cancer Center operating grant. VH is supported by a studentship from Terry Fox Foundation, SS is a recipient of a Canadian Institutes of Health Research Cancer Training Grant Award and ABD is a recipient of a Gerry Price Fellowship from the Cancer Research Society, Inc. AP is a recipient of the Canada Research Chair in Molecular Oncology.

  • Competing interests None to declare.

  • Provenance and peer review Not commissioned; externally peer reviewed.