Nicotine Induces the Up-regulation of the α7-Nicotinic Receptor (α7-nAChR) in Human Squamous Cell Lung Cancer Cells via the Sp1/GATA Protein Pathway

Background: Nicotine promotes the proliferation of human squamous cell lung cancer (SCC-L) via the 7-nicotinic receptor (nAChR). Results: Nicotine increases 7-nAChR expression via transcriptional mechanisms involving Sp1 and GATA proteins. Conclusion: Nicotine-induced up-regulation of 7-nAChR accelerates the growth of human SCC-L. Significance: SCC-L patients exposed to nicotine display fast growing lung tumors and worse clinical outcomes. Nicotine, the addictive component of cigarettes, promotes lung cancer proliferation via the 7-nicotinic acetylcholine receptor (7-nAChR) subtype. The present manuscript explores the effect of nicotine exposure on 7-nAChR levels in squamous cell carcinoma of the lung (SCC-L) in vitro and in vivo. Nicotine (at concentrations present in the plasma of average smokers) increased 7-nAChR levels in human SCC-L cell lines. Nicotine-induced up-regulation of 7-nAChR was confirmed in vivo by chicken chorioallantoic membrane models. We also observed that the levels of 7-nAChR in human SCC-L tumors (isolated from patients who are active smokers) correlated with their smoking history. Nicotine increased the levels of 7-nAChR mRNA and 7-nAChR transcription in human SCC-L cell lines and SCC-L tumors. Nicotine-induced up-regulation of 7-nAChR required GATA4 and GATA6. ChIP assays showed that nicotine induced the binding of GATA4 or GATA6 to Sp1 on the 7-nAChR promoter, thereby inducing its transcription and increasing its levels in human SCC-L. Our data are clinically relevant because SCC-L patients smoked for decades before being diagnosed with cancer. It may be envisaged that continuous exposure to nicotine (in such SCC-L patients) causes up-regulation of 7-nAChRs, which facilitates tumor growth and progression. Our results will also be relevant to many SCC-L patients exposed to nicotine via second-hand smoke, electronic cigarettes, and patches or gums to quit smoking.