Oncogenic KRas Suppresses Inflammation-Associated Senescence of Pancreatic Ductal Cells

被引：112
|
作者：
Lee, Kyoung Eun [1 ]
Bar-Sagi, Dafna [1 ,2 ]
机构：
[1] NYU, Sch Med, Cell & Mol Biol Program, New York, NY 10016 USA
[2] NYU, Sch Med, Dept Biochem, New York, NY 10016 USA
来源：
CANCER CELL | 2010年 / 18卷 / 05期
基金：
美国国家卫生研究院;
关键词：
NF-KAPPA-B; K-RAS; CELLULAR SENESCENCE; TUMOR SUPPRESSION; EPITHELIAL-CELLS; GENE-EXPRESSION; UP-REGULATION; IN-VIVO; CANCER; TWIST;
D O I：
10.1016/j.ccr.2010.10.020
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Mutational activation of KRas is the first and most frequently detected genetic lesion in pancreatic ductal adenocarcinoma (PDAC). However, the precise role of oncogenic KRas in the pathogenesis of PDAC is not fully understood. Here, we report that the endogenous expression of oncogenic KRas suppresses premature senescence in primary pancreatic duct epithelial cells (PDEC). Oncogenic KRas-mediated senescence bypass is conferred by the upregulation of the basic helix-loop-helix transcription factor Twist that in turn abrogates p16(INK4A) induction. Moreover, the KRas-Twist-p16(INK4A) senescence bypass pathway is employed in vivo to prevent inflammation-associated senescence of pancreatic ductal epithelium. Our findings indicate that oncogenic KRas could contribute to PDAC initiation by protecting cells from entering a state of permanent growth arrest.
引用
收藏
页码：448 / 458
页数：11
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