SWI/SNF蛋白PBRM1抑制VHL缺失驱动的肾透明细胞癌。
The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.
作者信息
Nargund Amrita M, Pham Can G, Dong Yiyu, Wang Patricia I, Osmangeyoglu Hatice U, Xie Yuchen, Aras Omer, Han Song, Oyama Toshinao, Takeda Shugaku, Ray Chelsea E, Dong Zhenghong, Berge Mathieu, Hakimi A Ari, Monette Sebastien, Lekaye Carl L, Koutcher Jason A, Leslie Christina S, Creighton Chad J, Weinhold Nils, Lee William, Tickoo Satish K, Wang Zhong, Cheng Emily H, Hsieh James J
机构信息
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
出版信息
Cell Rep. 2017 Mar 21;18(12):2893-2906. doi: 10.1016/j.celrep.2017.02.074.
PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.
PBRM1是透明细胞肾细胞癌（ccRCC）中仅次于VHL的第二常见突变基因。然而，PBRM1突变对肾肿瘤发生的生物学影响尚不清楚。在这里，我们发现肾脏特异性缺失Vhl和Pbrm1会导致双侧、多灶性、可移植的透明细胞肾癌，而单独缺失任何一个基因则不会。PBRM1的缺失放大了Vhl缺陷引起的HIF1和STAT3的转录输出。对小鼠和人类ccRCC的分析揭示了mTOR激活的趋同性，这是VHL和PBRM1基因失活后的第三个驱动事件。我们的研究报告了一种生理性临床前ccRCC小鼠模型，该模型概括了人类ccRCC中的体细胞突变，并为人类ccRCC的PBRM1突变亚型提供了机制和治疗方面的见解。
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