Abstract
AimsCholinergic signaling, particularly in response to non-physiological ligands like nicotine, stimulates carcinogenesis of a variety of tissue types including epithelia of the cervix uteri. Cholinergic signaling is mediated by nicotinic acetylcholine receptors (nAChRs), which are pentamers formed by subsets of 16 nAChR subunits. Recent literature suggests that single nucleotide polymorphisms (SNPs) of some of these subunits, notably alpha5, are risk factors for developing lung cancer in smokers as well as in non-smokers. Main methodsWe have studied the prevalence of four SNPs in the alpha5, alpha9, and beta1 subunits, which are expressed in cervical cells, in 456 patients with cervical cancers, precursor lesions, and healthy controls from two cohorts in Mexico. Key findingsA SNP in the alpha9 subunit, the G allele of rs10009228 (alpha9, A>G) shows a significant trend in the combined cohort, indicating that this allele constitutes a risk factor for neoplastic progression. The A allele of the SNP rs16969968 (alpha5, G>A), which correlates with the development of lung cancer, shows a non-significant trend to be associated with cervical lesions. Two other SNPs, rs55633891 (alpha9, C>T) and rs17856697 (beta1, A>G), did not exhibit a significant trend. SignificanceOur study points to a potential risk factor of cervical carcinogenesis with importance for DNA diagnosis and as a target for intervention.
Highlights
A necessary, but not sufficient, prerequisite for developing cancer of the cervix uteri is infection with high-risk human papillomaviruses (HPVs) (Munoz et al, 2003)
Studies of nicotinic acetylcholine receptors (nAChRs) in head and neck (H&N) and lung cancers, the sites directly exposed to tobacco smoke, established that nAChR signaling is involved in the etiology of these cancers, as nicotine and nitrosamines are powerful ligands and function as tumor promoters (Schuller, 1989; Maneckjee and Minna, 1990; Grando et al, 1995)
In addition to rs16969968 in alpha5, we concentrated on three single nucleotide polymorphisms (SNPs) that we identified in sequence databases for alpha9 and beta1, as alpha5, alpha9 and beta1 are among the five principal nAChR subunits that are strongly expressed in cervical cells (Calleja-Macias et al, 2009)
Summary
A necessary, but not sufficient, prerequisite for developing cancer of the cervix uteri is infection with high-risk human papillomaviruses (HPVs) (Munoz et al, 2003). Studies of nAChRs in head and neck (H&N) and lung cancers, the sites directly exposed to tobacco smoke, established that nAChR signaling is involved in the etiology of these cancers, as nicotine and nitrosamines are powerful ligands and function as tumor promoters (Schuller, 1989; Maneckjee and Minna, 1990; Grando et al, 1995). Activation of nAChRs in epithelial cells leads to calcium ion fluxes and affects signaling by calcium–calmodulin kinase II and the Ras/Raf-1/MEK1/ERK1/2 and JAK-2/STAT-3 pathways pointing to mechanisms beyond the traditional model for the carcinogenicity of tobacco smoke mediated by mutagenicity
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