CHRNA3/CHRNA5 and Lung Tumorigenesis
Open AccessPast genome-wide association studies (GWAS) looked for genes contributing to lung cancer. Of the genes identified, two key genes, CHRNA3 and CHRNA5, both located on Chromosome 15q25, encoding for the alpha 3 (α3) and alpha 5 (α5) subunits of nicotinic acetylcholine receptors (nAChR). As smoking is a significant risk factors in lung cancer, these genes were examined closely and single nucleotide polymorphisms (SNPs) in each of these genes were linked to elevated lung cancer risk in GWAS studies, as well as playing a role in the quantity smoked, nicotine dependence, the intensity of smoking and internal dosage exposure to nitrosamines. However, these studies found conflicting results regarding whether the link between the CHRNA3, CHRNA5 genes and lung cancer was direct or if it was indirectly associated by differences in smoking behavior. To expand on these studies, this research will use mouse models (CHRNA5 wild type, heterozygous, and knockout; CHRNA3 wild type and heterozygous, knockout is embryonic lethal) to determine the relationship of the CHRNA3 and CHRNA5 genes and the development of lung tumors (tumor multiplicity), tumor volume, and tumor burden following exposure to the carcinogenic metabolite of nicotine, 4- (methylnitrosamine)1-(3-pyridyl)-1-butanone (NNK). All mice will receive the same dosage of NNK via an Alzet micro-osmotic pump for seven days because we believed that CHRNA3 and CHRNA5 are the receptors for NNK. The removal of nicotine (epidemiology suggests that nicotine is not a carcinogen) and dose differences from the study will allow for us to look at cancer risk associated with the genes. There were no significant difference in the tumor multiplicities and tumor burdens between the genotypes for both CHRNA3 and CHRNA5. Individual tumor volumes were not significantly different between CHRNA3 wild-type and heterozygous mice but there was a significant increase in individual tumor volumes in CHRNA5 knockout mice in comparison to their wild-type and heterozygous littermates. Because of the tumor multiplicities and burdens being nearly equivalent for all the genotypes of the mice, there is no evidence that the NNK uses α3 and α5 nAChRs as receptors and thus the link between the SNPs in the CHRNA3 and CHRNA5 genes are not directly related to lung cancer.
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