title: Flcn-deficient renal cells are tumorigenic and sensitive to mTOR suppression.
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 (Flcnflox/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.
authors.affiliation: Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi 563099, China.
authors.forename: Mingsong
authors.initials: M
authors.lastname: Wu
authors.affiliation: Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Si
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Schoen
authors.affiliation: Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Guang-Qian
authors.initials: GQ
authors.lastname: Xiao
authors.affiliation: Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi 563099, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Li
authors.affiliation: NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, 169610, Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi 563099, China.|Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Guan
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Cell Biology and Genetics, Zunyi Medical University, Zunyi 563099, China.|Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jindong
authors.initials: J
authors.lastname: Chen
mesh_terms: D064591:Allografts; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018345:Mice, Knockout; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C526060:Bhd protein, mouse; C476078:FLCN protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: BHD; RCC; kidney cancer; mTOR; sirolimus