DNA damage induced by human CD40 ligand mutant promotes senescence and induces demethylation of GATA4 in lung cancer.
DNA damage induced by human CD40 ligand mutant promotes senescence and induces demethylation of GATA4 in lung cancer.
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人CD40配体突变体诱导的DNA损伤促进肺癌衰老并诱导GATA4去甲基化
DOI：
10.3892/or.2018.6310
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发表时间：
2018-05
期刊：
影响因子：
4.2
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Li Y;Wei Y;Yuan W;Huang Q;Zhao Y;Zhao W;Xu W;Wu J
CD 40的配体，称为CD 154或CD 40 L，是免疫刺激和抗癌活性的关键，但CD 40 L如何影响细胞衰老尚不清楚。因此，我们研究了膜稳定突变形式CD 40 L（CD 40 L-M），以探索CD 40阳性非小细胞肺癌细胞中的肿瘤生长和细胞衰老。我们发现表达CD 40 L-M的细胞具有衰老特征，包括细胞增殖和增大减少，SA-β-gal染色活性增加，以及几种细胞周期调节因子p53和p21的过表达。此外，在CD 40 L-M诱导的衰老细胞中，GATA 4的表达得到恢复，NF-κB信号通路被激活。机制分析表明，CD 40 L-M表达触发ATM/Chk 2 DNA损伤反应，介导细胞衰老和GATA 4激活。GATA 4的敲低逆转了CD 40 L-M诱导的衰老并降低了NF-κB活性。因此，CD 40 L-M有助于诱导CD 40阳性NSCLC细胞的细胞衰老，GATA 4是激活NF-κB通路的开关，NF-κB通路受DNA损伤反应（DDR）信号传导激酶的正调控。总的来说，CD 40 L-M诱导的衰老可能是肺癌细胞生长的障碍。
The ligand of CD40, known as CD154 or CD40L, is the key to immunostimulatory and anticancer activity, but how CD40L affects cellular senescence is unclear. Thus, we studied a membrane-stable mutant form CD40L (CD40L-M) to explore tumor growth and cellular senescence in CD40-positive NSCLC cells. We found that CD40L-M-expressing cells had senescent characteristics, including reduced cell proliferation and enlargement, increased SA-β-gal staining activity, and overexpression of several cell cycle regulators p53 and p21. In addition, expression of GATA4 was restored, and the NF-κB signaling pathway was activated in the CD40L-M-induced senescent cells. Mechanistic analyses revealed that CD40L-M expression triggered the ATM/Chk2 DNA damage response, which mediated cell senescence and GATA4 activation. Knockdown of GATA4 reversed CD40L-M-induced senescence and decreased NF-κB activity. Thus, CD40L-M contributes to induction of cell senescence in CD40-positive NSCLC cells, and GATA4 is a switch to activate the NF-κB pathway, which is positively regulated by DNA damage response (DDR) signaling kinases. Collectively, CD40L-M-induced senescence may be a barrier to the growth of lung cancer cells.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
4
作者：
Campisi, Judith
通讯作者：
Campisi, Judith
影响因子：
3.7
作者：
Ge H;Ni S;Wang X;Xu N;Liu Y;Wang X;Wang L;Song D;Song Y;Bai C
通讯作者：
Bai C
影响因子：
--
作者：
Heo JI;Kim W;Choi KJ;Bae S;Jeong JH;Kim KS
通讯作者：
Kim KS
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars