Wu Mingsong, Si Shuhui, Li Yan, Schoen Susan, Xiao Guang-Qian, Li Xueying, Teh Bin Tean, Wu Guan, Chen Jindong
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.
Oncotarget. 2015 Oct 20;6(32):32761-73. doi: 10.18632/oncotarget.5018.
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.
肿瘤抑制因子卵泡抑素（FLCN）的缺乏会导致人Birt-Hogg-Dubé综合征（BHD）相关肾细胞癌（RCC）中mTOR信号通路的激活。我们之前构建了一种肾远曲小管-集合管-髓袢特异性Flcn基因敲除（KO）小鼠模型（Flcnflox/flox/Ksp-Cre）。由于多囊肾和尿毒症的发展，该小鼠模型出生后仅能存活三周。这些基因敲除小鼠中出现的这些囊实性增生变化是否具有致瘤性或恶性尚不清楚。在本研究中，我们证明了小鼠肾远曲小管细胞中Flcn基因的破坏可导致这些细胞发生致瘤性转化，从而形成具有侵袭性组织学表型的同种异体移植瘤。与之前的报道一致，我们表明mTOR通路在这些Flcn缺陷的同种异体移植瘤和人UOK 257-1异种移植瘤的生长中起重要作用。我们进一步证明，mTOR抑制剂西罗莫司可抑制肿瘤生长，这表明mTOR抑制剂可能对控制FLCN缺陷型RCC有效，尤其是在BHD肾肿瘤发生过程中。
