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CHRNA5 as negative regulator of nicotine signaling in normal and cancer bronchial cells : effects on motility, migration and p63 expression

Krais, Annette M LU ; Hautefeuille, Agnès H; Cros, Marie-Pierre; Krutovskikh, Vladimir; Tournier, Jean-Marie; Birembaut, Philippe; Thépot, Amélie; Paliwal, Anupam; Herceg, Zdenko and Boffetta, Paolo, et al. (2011) In Carcinogenesis 32(9). p.95-1388
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... (More)

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.

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keywords
Bronchi, Calcium, Cell Line, Cell Movement, Humans, Lung Neoplasms, Membrane Proteins, Nerve Tissue Proteins, Nicotine, Receptors, Nicotinic, Signal Transduction, alpha7 Nicotinic Acetylcholine Receptor, Journal Article, Research Support, Non-U.S. Gov't
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Carcinogenesis
volume
32
issue
9
pages
8 pages
publisher
Oxford University Press
external identifiers
  • scopus:80052423131
ISSN
0143-3334
DOI
10.1093/carcin/bgr090
language
English
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no
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2b13223e-2f74-499d-b918-b4de8e7c8951
date added to LUP
2017-10-17 15:32:35
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2017-10-31 15:52:45
@article{2b13223e-2f74-499d-b918-b4de8e7c8951,
  abstract     = {<p>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.</p>},
  author       = {Krais, Annette M and Hautefeuille, Agnès H and Cros, Marie-Pierre and Krutovskikh, Vladimir and Tournier, Jean-Marie and Birembaut, Philippe and Thépot, Amélie and Paliwal, Anupam and Herceg, Zdenko and Boffetta, Paolo and Brennan, Paul and Hainaut, Pierre L},
  issn         = {0143-3334},
  keyword      = {Bronchi,Calcium,Cell Line,Cell Movement,Humans,Lung Neoplasms,Membrane Proteins,Nerve Tissue Proteins,Nicotine,Receptors, Nicotinic,Signal Transduction,alpha7 Nicotinic Acetylcholine Receptor,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {9},
  pages        = {95--1388},
  publisher    = {Oxford University Press},
  series       = {Carcinogenesis},
  title        = {CHRNA5 as negative regulator of nicotine signaling in normal and cancer bronchial cells : effects on motility, migration and p63 expression},
  url          = {http://dx.doi.org/10.1093/carcin/bgr090},
  volume       = {32},
  year         = {2011},
}