Anti-tumoral activity of the human-specific duplicated form of α7-nicotinic receptor subunit in tobacco-induced lung cancer progression

• Published in: Lung cancer (Amsterdam, Netherlands) Netherlands), 2019-02, Vol.128, p.134-144
• Main Authors: Cedillo, José Luis, Bordas, Anna, Arnalich, Francisco, Esteban-Rodríguez, Isabel, Martín-Sánchez, Carolina, Extremera, María, Atienza, Gema, Rios, Juan J., Arribas, Raquel L., Montiel, Carmen
• Format: Article
• Language: English
• Subjects: alpha7 Nicotinic Acetylcholine Receptor - genetics; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Carcinoma, Non-Small-Cell Lung - etiology; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Disease Models, Animal; Disease Progression; Disease Susceptibility; dupα7 Nicotinic receptor subunit; Epithelial-Mesenchymal Transition - genetics; Gene Duplication; Gene Expression; Heterografts; Humans; Lung Neoplasms - etiology; Lung Neoplasms - pathology; Mice; Nicotine; Nitrosamines; Non-small cell lung cancer; Smoking - adverse effects; Tobacco smoke; α7 Nicotinic acetylcholine receptor
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2018.12.029

•A novel anti-tumor function for the human-specific duplicated CHRFAM7A gene in NSCLC.•CHRFAM7A encodes for dupα7, a duplicated form of the α7 nicotinic receptor subunit.•Dupα7 exhibits its anti-tumor activity in human NSCLC, both in vitro and in vivo.•Dupα7 inhibits the tobacco-activated oncogenic function of the ancestral α7 protein. Objectives: Tobacco smoking is strongly correlated with the onset and progression of non-small cell lung cancer (NSCLC). By activating α7 nicotinic acetylcholine receptors (α7-nAChRs) in these tumors nicotine and its tobacco-derived nitrosamine, NNK, contribute to these oncogenic processes. Here, we investigated whether the human-specific duplicated form of the α7-nAChR subunit (dupα7) behaves as an endogenous negative regulator of α7-nAChR-mediated tumorigenic activity induced by tobacco in NSCLC cells, similarly to its influence on other α7-nAChR-controlled functions in non-tumor cells. Methods: Two human NSCLC cell lines, lung adenocarcinoma (A549) and squamous cell carcinoma of the lung (SK-MES-1), both wild-type or with stable overexpression of dupα7 (A549dupα7 or SK-MES-1dupα7), were used to investigate in vitro anti-tumor activity of dupα7 on nicotine- or NNK-induced tumor progression. For this purpose, migration, proliferation or epithelial-mesenchymal transition (EMT) were examined. The anti-tumor effect of dupα7 on nicotine-promoted tumor growth, proliferation or angiogenesis was also assessed in vivo in an athymic mouse model implanted with A549dupα7 or A549 xenografts. Results: Overexpression of dupα7 in both cell lines almost completely suppresses the in vitro tumor-promoting effects induced by nicotine (1 μM) or NNK (100 nM) in wild-type cells. Furthermore, in mice receiving nicotine, A549dupα7 xenografts show: (i) a significant reduction of tumor growth, and (ii) decreased expression of cell markers for proliferation (Ki67) or angiogenesis (VEGF) compared to A549 xenografts. Conclusion: Our study demonstrates, for the first time, the in vitro and in vivo anti-tumor capacity of dupα7 to block the α7-nAChR-mediated tumorigenic effects of tobacco in NSCLC, suggesting that up-regulation of dupα7 expression in these tumors could offer a potential new therapeutic target in smoking-related cancers.