| Literature DB >> 28329682 |
Amrita M Nargund1, Can G Pham1, Yiyu Dong1, Patricia I Wang1, Hatice U Osmangeyoglu2, Yuchen Xie3, Omer Aras4, Song Han1, Toshinao Oyama1, Shugaku Takeda1, Chelsea E Ray1, Zhenghong Dong1, Mathieu Berge1, A Ari Hakimi5, Sebastien Monette6, Carl L Lekaye7, Jason A Koutcher8, Christina S Leslie2, Chad J Creighton9, Nils Weinhold10, William Lee10, Satish K Tickoo11, Zhong Wang12, Emily H Cheng13, James J Hsieh14.
Abstract
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.Entities:
Keywords: HIF1; MTOR; PBRM1; STAT3; VHL; ccRCC; epigenetics; genetics; kidney cancer; mouse tumor model
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Year: 2017 PMID： 28329682 PMCID： PMC5431084 DOI： 10.1016/j.celrep.2017.02.074
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423