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

// Mingsong Wu 1, * , Shuhui Si 2, * , Yan Li 3 , Susan Schoen 2 , Guang-Qian Xiao 4 , Xueying Li 1 , Bin Tean Teh 5 , Guan Wu 1, 4 , Jindong Chen 1, 2 1 Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi 563099, China 2 Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA 3 State Key Laboratory of Bioactive Substances and Functions of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China 4 Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA 5 NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, 169610, Singapore * These authors have contributed equally to this work Correspondence to: Jindong Chen, e-mail: Jindong_chen@URMC.rochester.edu Guan Wu, e-mail: guan_wu@URMC.rochester.edu Keywords: BHD, RCC, kidney cancer, mTOR, sirolimus Received: July 17, 2015      Accepted: September 09, 2015      Published: September 21, 2015 ABSTRACT Deficiency of tumor suppressor FLCN leads to the activation of the mTOR signaling pathway in human BHD-associated renal cell carcinomas (RCC). We have previously developed a renal distal tubule-collecting duct-Henle's loop-specific Flcn knockout (KO) mouse model ( Flcn flox/flox / Ksp-Cre ). This mouse model can only survive for three weeks after birth due to the development of polycystic kidney and uremia. Whether these cystic solid hyperplasia changes seen in those KO mice are tumorigenic or malignant is unknown. In this study, we demonstrated that genetic disruption of Flcn in mouse kidney distal tubule cells could lead to tumorigenic transformation of these cells to develop allograft tumors with an aggressive histologic phenotype. Consistent with previous reports, we showed that the mTOR pathway plays an important role in the growth of these Flcn-deficient allograft and human UOK 257-1 xenograft tumors. We further demonstrated that the mTOR inhibitor, sirolimus, suppresses the tumor's growth, suggesting that mTOR inhibitors might be effective in control of FLCN-deficient RCC, especially in BHD renal tumorigenesis.