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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.
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 Of the relevant studies, 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. Nonotin increased the levels of a5-nAChR mRNA and protein in NSCLC cell lines and activated the JAK2 / STAT3 signaling cascade. Nototine-induced activation of JAK2 / STAT3 signaling was inhibited by 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. ysilencingSTAT3 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.