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.
Keywords:
BHD; RCC; kidney cancer; mTOR; sirolimus.
MeSH terms
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Allografts
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Animals
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Antineoplastic Agents / pharmacology*
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Carcinoma, Renal Cell / drug therapy*
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Carcinoma, Renal Cell / enzymology*
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / pathology
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Gene Expression Regulation, Neoplastic
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Genetic Predisposition to Disease
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Humans
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Kidney Neoplasms / drug therapy*
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Kidney Neoplasms / enzymology*
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Kidney Neoplasms / genetics
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Kidney Neoplasms / pathology
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Mice, Knockout
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Mice, Nude
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Molecular Targeted Therapy
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Phenotype
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins / deficiency*
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Proto-Oncogene Proteins / genetics
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Signal Transduction / drug effects
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Sirolimus / pharmacology*
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
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Time Factors
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Tumor Burden / drug effects
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Tumor Suppressor Proteins / deficiency*
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Tumor Suppressor Proteins / genetics
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Bhd protein, mouse
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FLCN protein, human
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Tumor Suppressor Proteins
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MTOR protein, human
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Sirolimus