Minor allele of rs1057317 polymorphism in TLR4 is associated with increased risk of Helicobacter pylori -induced gastric cancer.

Background: Helicobacter pylori (HP) plays a significant role in the carcinogenesis of gastric cancer (GC), the second leading cause of cancer-related death worldwide. The aim of this study was to investigate the effect of rs1057317 polymorphism on the interaction between microRNA-034a (miR-034a) and toll-like receptor 4 (TLR4), and their involvement in the HP-associated GC.

Methods: Computation analyses, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and luciferase assays were performed to identify potential miRNAs involved in the carcinogenesis of HP-induced GC. Subsequently, the effect of miR-34a and recombinant TNFα-interacting protein α (rTip-α) on the expression of TLR4, interleukin (IL)-6, and tumor necrosis factor α (TNF-α) was measured.

Results: Three hundred and twelve HP-positive GC patients (HP+ GC) and 380 HP-negative GC patients (HP- GC) were enrolled into this study. It was found that, in HP-positive patient, the AA genotype of the rs1057317 polymorphism was closely associated with the risk of GC (95% confidence interval, 1.12 to 2.70; odds ratio, 1.74; P = 0.0129). Furthermore, between the HP+ GC and HP- GC groups, miR-34a was the only miRNA showing a significantly different expression. Subsequently, TLR4 was identified as a target gene of miR-34a. Interestingly, miR-34a evidently reduced the expression of TLR4 3'-untranslated region (3'-UTR) containing the C allele of the rs1057317 polymorphism, but the TLR4 3'-UTR containing the A allele in the rs1057317 was not affected by miR-34a. In addition, the expression of IL-6 and TNF-α was significantly downregulated by miR-34a, but increased by rTip-α. Both miR-34a and rTip-α could enhance the viability of cells, although the effect of rTip-α was stronger.

Conclusion: The data of this study suggested that the rs1057317 polymorphism in the miR-34a binding site of TLR4 may predict the risk of HP-induced GC.