title: CHRNA5 as negative regulator of nicotine signaling in normal and cancer bronchial cells: effects on motility, migration and p63 expression.
abstract: Genome-wide association studies have linked lung cancer risk with a region of chromosome 15q25.1 containing CHRNA3, CHRNA5 and CHRNB4 encoding α3, α5 and β4 subunits of nicotinic acetylcholine receptors (nAChR), respectively. One of the strongest associations was observed for a non-silent single-nucleotide polymorphism at codon 398 in CHRNA5. Here, we have used pharmacological (antagonists) or genetic (RNA interference) interventions to modulate the activity of CHRNA5 in non-transformed bronchial cells and in lung cancer cell lines. In both cell types, silencing CHRNA5 or inhibiting receptors containing nAChR α5 with α-conotoxin MII exerted a nicotine-like effect, with increased motility and invasiveness in vitro and increasing calcium influx. The effects on motility were enhanced by addition of nicotine but blocked by inhibiting CHRNA7, which encodes the homopentameric receptor α7 subunit. Silencing CHRNA5 also decreased the expression of cell adhesion molecules P120 and ZO-1 in lung cancer cells as well as the expression of DeltaNp63α in squamous cell carcinoma cell lines. These results demonstrate a role for CHRNA5 in modulating adhesion and motility in bronchial cells, as well as in regulating p63, a potential oncogene in squamous cell carcinoma.
authors.affiliation: Group of Molecular Carcinogenesis, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Krais
authors.forename: Agnès H
authors.initials: AH
authors.lastname: Hautefeuille
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Cros
authors.forename: Vladimir
authors.initials: V
authors.lastname: Krutovskikh
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Tournier
authors.forename: Philippe
authors.initials: P
authors.lastname: Birembaut
authors.forename: Amélie
authors.initials: A
authors.lastname: Thépot
authors.forename: Anupam
authors.initials: A
authors.lastname: Paliwal
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Hainaut
mesh_terms: D001980:Bronchi / Q000166:cytology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000473:pathology; D008565:Membrane Proteins / Q000032:analysis*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009538:Nicotine / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D002118:Calcium; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009538:Nicotine; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C447158:CHRNA5 protein, human; C081876:CKAP4 protein, human; C579167:Chrna7 protein, human