Anti-tumoral activity of the human-specific duplicated form of α7-nicotinic receptor subunit in tobacco-induced lung cancer progression. (February 2019)

• Record Type: Journal Article
• 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
• Is Part Of: Lung cancer. Volume 128(2019)
• Page Start: 134
• Page End: 144
• Publication Date: 2019-02
• Subjects: α7-nAChR α7 nicotinic acetylcholine receptor subtype -- dupα7 human-specific duplicated form of the α7-nAChR subunit -- EMT epithelial-mesenchymal transition -- ERK extracellular signal-regulated kinase -- FBS fetal bovine serum -- HRP horseradish peroxidase -- IHC immunohistochemistry -- MEK mitogen-activated protein kinase -- NNK nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyrydyl)-1-butanone -- NSCLC non-small cell lung cancer -- p90RSK MAPK-activated protein kinase-1 -- PVDF polyvinylidene difluoride -- qPCR real-time quantitative PCR -- Raf-1 RAF proto-oncogene serine/threonine-protein kinase -- Rb retinoblastoma tumor suppressor protein -- SCLC small cell lung cancer -- VEGF vascular endothelial grown factor; α7 Nicotinic acetylcholine receptor -- dupα7 Nicotinic receptor subunit -- Non-small cell lung cancer -- Tobacco smoke -- Nicotine -- Nitrosamines; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2018.12.029
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: 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. Abstract: 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 (A549 dupα7 or SK-MES-1 dupα7 ), 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 A549 dupα7 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, A549 dupα7 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.