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

Lung Cancer. 2019 Feb:128:134-144. doi: 10.1016/j.lungcan.2018.12.029. Epub 2018 Dec 28.

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 (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.

Keywords: Nicotine; Nitrosamines; Non-small cell lung cancer; Tobacco smoke; dupα7 Nicotinic receptor subunit; α7 Nicotinic acetylcholine receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Duplication*
  • Gene Expression
  • Heterografts
  • Humans
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / pathology*
  • Mice
  • Smoking / adverse effects*
  • alpha7 Nicotinic Acetylcholine Receptor / genetics*
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism

Substances

  • alpha7 Nicotinic Acetylcholine Receptor