title: Nicotine-Mediated Regulation of Nicotinic Acetylcholine Receptors in Non-Small Cell Lung Adenocarcinoma by E2F1 and STAT1 Transcription Factors.
abstract: Cigarette smoking is the major risk factor for non-small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the addictive component of tobacco smoke, can induce proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, and survival in NSCLC cell lines, as well as growth and metastasis of NSCLC in mice. This nicotine-mediated tumor progression is facilitated through activation of nicotinic acetylcholine receptors (nAChRs), specifically the α7 subunit; however, how the α7 nAChR gene is regulated in lung adenocarcinoma is not fully clear. Here we demonstrate that the α7 nAChR gene promoter is differentially regulated by E2F and STAT transcription factors through a competitive interplay; E2F1 induces the promoter, while STAT transcription factors repress it by binding to an overlapping site at a region -294 through -463bp upstream of the transcription start site. Treatment of cells with nicotine induced the mRNA and protein levels of α7 nAChR; this could be abrogated by treatment with inhibitors targeting Src, PI3K, MEK, α7 nAChR, CDK4/6 or a disruptor of the Rb-Raf-1 interaction. Further, nicotine-mediated induction of α7 nAChR was reduced when E2F1 was depleted and in contrast elevated when STAT1 was depleted by siRNAs. Interestingly, extracts from e-cigarettes, which have recently emerged as healthier alternatives to traditional cigarette smoking, can also induce α7 nAChR expression in a manner similar to nicotine. These results suggest an autoregulatory feed-forward loop that induces the levels of α7 nAChR upon exposure to nicotine, which enhances the strength of the signal. It can be imagined that such an induction of α7 nAChR contributes to the tumor-promoting functions of nicotine.
authors.affiliation: Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.|Cancer Biology PhD Program, Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Courtney
authors.initials: C
authors.lastname: Schaal
authors.affiliation: Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors.forename: Srikumar
authors.initials: S
authors.lastname: Chellappan
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009363:Neoplasm Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6