The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.
The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.
复制标题
DOI：
10.1016/j.celrep.2017.02.074
复制
发表时间：
2017-03-21
期刊：
影响因子：
8.8
通讯作者：
Hsieh JJ
中科院分区：
文献类型：
--
作者：
Nargund AM;Pham CG;Dong Y;Wang PI;Osmangeyoglu HU;Xie Y;Aras O;Han S;Oyama T;Takeda S;Ray CE;Dong Z;Berge M;Hakimi AA;Monette S;Lekaye CL;Koutcher JA;Leslie CS;Creighton CJ;Weinhold N;Lee W;Tickoo SK;Wang Z;Cheng EH;Hsieh JJ
PBRM1是肾透明细胞癌中仅次于VHL的第二大突变基因。然而，PBRM1突变对肾脏肿瘤发生的生物学影响尚不清楚。在这里，我们发现VHL和PBRM1的肾脏特异性缺失，而不是两个基因中的任何一个单独缺失，会导致双侧、多灶性、可移植的透明细胞肾癌。PBRM1缺失使VHL缺乏引起的HIF1和STAT3转录产物增加。对小鼠和人类ccRCC的分析表明，mTOR激活的趋同，代表了继VHL和PBRM1基因失活之后的第三个驱动事件。我们的研究报告了一个生理性的临床前ccRCC小鼠模型，它概括了人ccRCC的体细胞突变，并提供了对PBRM1突变的人ccRCC亚型的机制和治疗方面的见解。Nargund等人的研究成果。在小鼠和人类透明细胞肾癌的发病机制中呈现一个三步走的过程。在失去VHL后，SWI/SNF肿瘤抑制蛋白PBRM1/BAF180的丢失进一步激活了小鼠肾脏中的HIF1/STAT3信号，并将mTORC1激活定位为首选的第三驱动事件。
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. Nargund et al. present a three-step process in the pathogenesis of mouse and human clear cell kidney cancer. After the loss of VHL, the loss of SWI/SNF tumor suppressor protein PBRM1/BAF180 further activates HIF1/STAT3 signaling in mouse kidney and positions mTORC1 activation as the preferred third driver event.