Abstract
IL23/Th17 axis acts as an inflammatory pathway in gastric carcinogenesis. MicroRNA- (miRNA-) binding site single-nucleotide polymorphisms (SNPs) of inflammatory genes may alter gastric cancer (GC) susceptibility. In this study, four miRNA binding site SNPs (rs3748067 of IL17A, rs887796, rs1468488 of IL17RA, and rs10889677 of IL23R) were genotyped from 500 patients and 500 controls. Unconditional logistic regression analyses and multifactor dimensionality reduction software were used to evaluate the relationships of SNPs with GC and gene-environment interactions, respectively. Quantitative real-time PCR, Western blot analysis, and luciferase report gene assay were applied for function verification. We found that CT (ORadj = 0.59; 95% CI: 0.44–0.79), CT + TT (ORadj = 0.58; 95% CI: 0.43–0.77) genotypes, and T allele (ORadj = 0.77; 95% CI: 0.47–0.80) of rs3748067 reduced GC risk; the rs10889677 CC genotype (ORadj = 2.22; 95% CI: 1.27–3.87) and C allele (ORadj = 1.24; 95% CI: 1.02–1.52) increased GC risk. A meaningful interaction among ever smoked, family history of GC, and rs3748068 could intensify GC risk by 2.25-fold. Functional tests demonstrated the inhibitory effect of miR-10a-3p on IL17A expression in SGC-7901 cells. These results suggested that miRNA binding site SNPs within IL23/Th17 inflammatory pathway genes and their interactions with environmental factors could be associated with GC risk.
Highlights
Gastric cancer (GC) is a frequently diagnosed cancer with an estimated number of 951,600 new cases and 723,100 deaths worldwide [1]
We found that miRNA binding site single-nucleotide polymorphisms (SNPs) within IL23/T helper 17 (Th17) inflammatory pathway genes were associated with GC risk in Chinese population
The CT genotype (ORadj = 0.59; 95% CI: 0.44–0.79) and T allele (ORadj = 0.77; 95% CI: 0.47–0.80) of IL17A rs3748067 were associated with decreased GC risk; the effect was more evident in men (ORadj = 0.55; 95% CI: 0.40–0.75), age > 50 years (ORadj = 0.57; 95% CI: 0.41–0.78), ever smoked (ORadj = 0.43; 95% CI: 0.29–0.63), ever drank (ORadj = 0.50; 95% CI: 0.31–0.79), and without family history of GC (ORadj = 0.58; 95% CI: 0.43–0.79), while individuals carrying the IL23R rs10889677 CC genotype (ORadj = 2.22; 95% CI: 1.27–3.87) and C allele (ORadj = 1.24; 95% CI: 1.02– 1.52) had higher GC risk
Summary
Gastric cancer (GC) is a frequently diagnosed cancer with an estimated number of 951,600 new cases and 723,100 deaths worldwide [1]. Despite the declining trends of the incidence and mortality rates, it still ranked as the second leading cause of cancer death among both men and women in China in 2015 [2]. Gastric carcinogenesis is a multifactorial and multistage process. It is accepted that biological factors in which Helicobacter pylori (H. pylori) infection-induced inflammation account for the main role [3], a complex network interaction among bacterial factors, host factors, and environmental factors responds to inflammation, and epigenetic changes may occur and eventually lead to inflammation-related oncogenesis [4].
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