标题：Reciprocal activation of alpha 5-nAChR and STAT3 in nicotine-induced human lung cancer cell proliferation
作者：Zhang, Yao; Jia, Yanfei; Li, Ping; Li, Huanjie; Xiao, Dongjie; Wang, Yunshan; Ma, Xiaoli
作者机构：[Zhang, Y] Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan, 250100, China;[ Jia, Y] Central Laboratory, Jinan Cent 更多
通讯作者地址：[Wang, YS; Ma, XL]Shandong Univ, Jinan Cent Hosp, Cent Lab, Jinan 250100, Shandong, Peoples R China.
关键词：α5-nAChR;STAT3;Cell proliferation;Nicotine;Non-small cell lung cancer
摘要：Cigarette smoking is the top environmental risk factor for lung cancer.Nicotine,the adclictive component of cigarettes,induces lung cancer cell proliferation,invasion and migration via the activation of nicotinicacetylcholine receptors (nAChRs).Genome-wide association studies (GWAS) show that CHRNA5 gene encoding α5-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 α5-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 α5-nAChR mRNA and protein in NSCLC cell lines and activated the JAK2/STAT3 signaling cascade.Nicotine-induced activation of JAK2/STAT3 signaling was inhibited by the silencing of α5-nAChR.Characterization of the CHRNA5 promoter revealed four STAT3-response elements.ChIP assays confirmed that the CHRNA5 promoter contains STAT3 binding sites.By silencing STAT3 expression,nicotine-induced upregulation of αS-nAChR was suppressed.Downregulation of αS-nAChR and/or STAT3 expression inhibited nicotine-induced lung cancer cell proliferation.These results suggest that there is a feedback loop between α5-nAChR and STAT3 that contributes to the nicotine-induced tumor cell proliferation,which indicates that α5-nAChR is an important therapeutic target involved in tobacco-associated lung carcinogenesis.