CHRNA5 variants related to nicotine sensitivity in lung cancer in vitro

Nicotine, the chemical compound which causes cigarette addiction, could be responsible for some lung cancers. Evidence for genetic influence on smoking behavior and nicotine dependence has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Recently, the locus containing two genes encoding nicotine acetylcholine receptor subunits, CHRNA3 and CHRNA5, were shown to be associated with lung cancer risk. Here we performed to directly test whether variants at codon 398 (D398N) of CHRNA5 with an effect on nicotine sensitivity in lung cancer cells in vitro. The results showed that nicotine accelerated cell proliferation of lung cancer in time dependent and dose dependent manners and there were different optimal concentrations of nicotine on cell proliferations of lung cancer with CHRNA5 SNP398 variants. Expression of CHRNA5 mRNA was increased in lung cancer cell after nicotine treatment. These results suggest that CHRNA5 variants may be related to nicotine sensitivity in lung cancer.

I. Introduction

Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypic ligand-gated ion channels that mediate fast synaptic transmission [1]. Neuronal nAChRs are pentameric proteins comprising either combinations of two different types of subunit ( and ) or five copies of the same a subunit symmetrically arranged around a central ion pore. The nAChR gene family include nine proteins designated as a subunits and three proteins designated as subunits [2], [3]. Nicotinic acetylcholine receptors are essential for neuromuscular signaling and are also expressed in non-neuronal tissues (such as lung cancer, etc), where their function is less clear [4]. The cholinergic nicotinic receptor subunit genes (CHRN), CHRNA5-CHRNA3-CHRNB4 cluster, are of further interest because of recent reports of significant association with lung cancer [5]–[7], a disease for which cigarette smoking is known to be the major risk factor.