Expression patterns for nicotinic acetylcholine receptor subunit genes in smoking-related lung cancers
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Anna Bordas1,5,*, José Luis Cedillo1,5,*, Francisco Arnalich2,5,#, Isabel Esteban-Rodriguez3,5, Laura Guerra-Pastrián3,5, Javier de Castro4,5, Carolina Martín-Sánchez1,5, Gema Atienza1,5, Carmen Fernández-Capitan2,5, Juan José Rios2,5 and Carmen Montiel1,5,#
1Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain
2Servicios de Medicina Interna, Hospital Universitario La Paz, Madrid, Spain
3Anatomía Patológica, Hospital Universitario La Paz, Madrid, Spain
4Oncología Médica, Hospital Universitario La Paz, Madrid, Spain
5Instituto de Investigaciones Sanitarias IdiPAZ, Madrid, Spain
*Co-first authors, These authors contributed equally to this work
#These authors have contributed equally to the direction of the work
Carmen Montiel, email: [email protected]
Keywords: nAChRs, NSCLC, squamous cell carcinoma of the lung, lung adenocarcinoma, tobacco
Received: April 07, 2017 Accepted: June 17, 2017 Published: July 04, 2017
Cigarette smoking is associated with increased risk for all histologic types of lung cancer, but why the strength of this association is stronger for squamous cell carcinoma than adenocarcinoma of the lung (SQC-L, ADC-L) is not fully understood. Because nicotine and tobacco-specific nitrosamines contribute to carcinogenesis by activating nicotinic acetylcholine receptors (nAChRs) on lung tumors and epithelial cells, we investigated whether differential expression of nAChR subtypes in these tumors could explain their different association with smoking. Expression of nAChR subunit genes in paired tumor and non-tumor lung specimens from 40 SQC-L and 38 ADC-L patients was analyzed by quantitative PCR. Compared to normal lung, both tumors share: i) transcriptional dysregulation of CHRNA3/CHRNA5/CHRNB4 (α3, α5, β4 subunits) at the chromosomal locus that predisposes to lung cancer; and ii) decreased expression of CHRFAM7A (dupα7 subunit); this last subunit negatively modulates α7-nAChR activity in oocytes. In contrast, CHRNA7 (α7 subunit) expression was increased in SQC-L, particularly in smokers and non-survivors, while CHRNA4 (α4 subunit) expression was decreased in ADC-L. Thus, over-representation of cancer-stimulating α7-nAChR in SQC-L, also potentiated by smoking, and under-representation of cancer-inhibiting α4β2-nAChR in ADC-L could explain the different tobacco influences on the tumorigenic process in each cancer type.
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