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Reciprocal activation ofα5-nAChR and STAT3 in nicotine-induced human lung cancer cell proliferation

查看全文 作　　者：Yao [1]Zhang;Yanfei [1]Jia;Ping [1]Li;Huanjie [1,2]li;Dongjie [1]Xiao;[1]YunshanWang;Xiaoli [1]Ma 高影响力作者 机构地区：[1]Central Laboratory,Jinan Central Hospital Affiliated to Shandong University,Jinan 250100,China;[2]State Key Laboratory of Microbial Technology,Shandong University,Jinan 250100,China高影响力机构 出　　处：《Journal of Genetics and Genomics》索引2017年第44卷第7期,共8页高影响力期刊 基　　金：funded by grants from the National Natural Science Foundation of China(Nos.81272588,81602593,31671468 and 31672286);the Shandong Provincial Natural Science Foundation of China(No.ZR2012HM061) 摘　　要：Cigarette smoking is the top environmental risk factor for lung cancer.Nicotine,the addictive component of cigarettes,induces lung cancer cell proliferation,invasion and migration via the activation of nicotinic acetylcholine receptors(nAChRs).Genome-wide association studies(GWAS)show that CHRNA5 gene encoding a5-nAChR is especially relevant to lung cancer.However,the mechanism of this subunit in lung cancer is not clear.In the present study,we demonstrate that the expression of a5-nAChR is correlated with phosphorylated STAT3(pSTAT3)expression,smoking history and lower survival of non-small cell lung cancer(NSCLC)samples.Nicotine increased the levels of a5-nAChR mRNA and protein in NSCLC celllinesandactivatedtheJAK2/STAT3 signaling cascade.Nicotine-induced activation of JAK2/STAT3signaling was inhibited by the silencing of a5-nAChR.Characterization of the CHRNA5 promoter revealed four STAT3-response elements.ChIP assays confirmed that the CHRNA5 promoter contains STAT3 binding sites.BysilencingSTAT3 expression,nicotine-induced upregulation of a5-nAChR was suppressed.Downregulation of a5-nAChR and/or STAT3 expression inhibited nicotine-induced lung cancer cell proliferation.These results suggest that there is a feedback loop between a5-nAChR and STAT3 that contributestothenicotine-inducedtumor cell proliferation,which indicates that a5-nAChR is an important therapeutic target involved in tobacco-associated lung carcinogenesis. 关 键 词：肺癌 尼古丁 治疗方法 医学研究
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