Disruption of tubular Flcn expression as a mouse model for renal tumor induction

Jindong Chen, Dachuan Huang, Isabelle Rubera, Kunihiko Futami, Pengfei Wang, Peter Zickert, Sok Kean Khoo, Karl Dykema, Ping Zhao, David Petillo, Brian Cao, Zhongfa Zhang, Shuhui Si, Susan R. Schoen, Ximing J. Yang, Ming Zhou, Guang Qian Xiao, Guan Wu, Magnus Nordenskjöld, Michel TaucBart O. Williams, Kyle A. Furge, Bin Tean Teh

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The study of kidney cancer pathogenesis and its treatment has been limited by the scarcity of genetically defined animal models. The FLCN gene that codes for the protein folliculin, mutated in Birt-Hogg-Dubé syndrome, presents a new target for mouse modeling of kidney cancer. Here we developed a kidney-specific knockout model by disrupting the mouse Flcn in the proximal tubules, thus avoiding homozygous embryonic lethality or neonatal mortality, and eliminating the requirement of loss of heterozygosity for tumorigenesis. This knockout develops renal cysts and early onset (6 months) of multiple histological subtypes of renal neoplasms featuring high tumor penetrance. Although the majority of the tumors were chromophobe renal cell carcinomas in affected mice under 1 year of age, papillary renal cell carcinomas predominated in the kidneys of older knockout mice. This renal neoplasia from cystic hyperplasia at 4 months to high-grade renal tumors by 16 months represented the progression of tumorigenesis. The mTOR and TGF-β signalings were upregulated in Flcn-deficient tumors, and these two activated pathways may synergetically cause renal tumorigenesis. Treatment of knockout mice with the mTOR inhibitor rapamycin for 10 months led to the suppression of tumor growth. Thus, our model recapitulates human Birt-Hogg-Dubé kidney tumorigenesis, provides a valuable tool for further study of Flcn-deficient renal tumorigenesis, and tests new drugs/approaches to their treatment.

Original languageEnglish (US)
Pages (from-to)1057-1069
Number of pages13
JournalKidney international
Volume88
Issue number5
DOIs
StatePublished - Nov 1 2015

Keywords

  • BHD
  • FLCN
  • Gene targeting
  • Kidney cancer
  • MTOR
  • Mouse model
  • RCC
  • TGF-β

ASJC Scopus subject areas

  • Nephrology

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  • Cite this

    Chen, J., Huang, D., Rubera, I., Futami, K., Wang, P., Zickert, P., Khoo, S. K., Dykema, K., Zhao, P., Petillo, D., Cao, B., Zhang, Z., Si, S., Schoen, S. R., Yang, X. J., Zhou, M., Xiao, G. Q., Wu, G., Nordenskjöld, M., ... Teh, B. T. (2015). Disruption of tubular Flcn expression as a mouse model for renal tumor induction. Kidney international, 88(5), 1057-1069. https://doi.org/10.1038/ki.2015.177