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Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations.
Cancer Cell ( IF 50.3 ) Pub Date : 2017-09-11 , DOI: 10.1016/j.ccell.2017.08.006
Michelle Vaz , Stephen Y. Hwang , Ioannis Kagiampakis , Jillian Phallen , Ashwini Patil , Heather M. O'Hagan , Lauren Murphy , Cynthia A. Zahnow , Edward Gabrielson , Victor E. Velculescu , Hariharan P. Easwaran , Stephen B. Baylin

We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.

中文翻译:

慢性香烟烟雾诱导的表观基因组学变化先于支气管上皮细胞被KRAS突变敏化为单步转化。

我们定义了慢性香烟烟雾诱导的时间依赖性表观遗传学改变如何使人类支气管上皮细胞对单个癌基因的转化敏感。烟雾引起的染色质变化包括最初的基因抑制性多梳标记,后来在10个月后表现出异常的DNA甲基化。此时,细胞表现出上皮到间充质改变,不依赖贴壁的生长,以及上调的RAS / MAPK信号,同时使高甲基化基因沉默,这些基因通常会抑制这些途径,并与吸烟相关的非小细胞肺癌有关。现在,这些细胞在没有任何驱动基因突变的情况下,通过引入单个KRAS突变而转化,并在小鼠中形成了腺鳞状肺癌。因此,
更新日期:2017-09-11
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