The Role Of H. Pylori, Inflammation Cytokine And Related MicroRNA Terget SNP In Gastric Cancer

Background and AimsGastric cancer is one of the most harmful to the health in the world. Most of scholars had the consensus that the carcinogenesis of gastric cancer is due to the synergetic effect of biologic factors, genetic factors and environmental factors. Meanwhile, it is also a multi-stage and multi-step process. Helicobacter pylori (H. pylori) is the most important biologic factor. The mechanism is H. pylori intections caused gastric mucosal layers, edema, debaucjed, bleeding congestion and neutral leucocyte infiltration. Then it goes though the process of "chronic gastritis-intestinal metaplasia-dysplasia-gastric cancer". A lot of epidemiological data showed the obvious association between H. pylori intections and gastric cancer. Many experimental studies also reached conclusion that H. pylori eradication therapy could reduce the risk of incidence of gastric cancer. The clinical inflammation caused by H. pylori infection is mediated by a series of inflammatory cytokines. The inflammatory cytokines (Pro-inflammatory cytokine and Anti-inflammatory cytokines) play an important modulatory role in the continuence and development of inflammation. It regulates the starting and the ending of immune response and causes pathophysiological change of stomach after breaking the original regulation balance in our bodies. At last gastric cancer happened.The molecular mechanism of gastric cancer is not clear. It has been recently discovered that microRNA plays a very important role in the gene expression regulation. MicroRNA could cause disorder of gene expression and induce cancer. It will change gene regulation if microRNA target sequence of the tumor related genes mutations. So it is an important aspect in the studies of molecular mechanism of gastric cancer.The objectives of the study have three aspects. (1) We could validate significant association between H. pylori eradication and reduction for the risk of gastric cancer incidence. Is H. pylori eradication therapy an effect clinical measure to reduce the risk of gastric cancer? It would get a real and credible answer by this study. (2) It would confirme the association between inflammatory cytokines and susceptibility of gastric cancer by the case-control familial comparative study. Then it could explore further role of inflammatory cytokines in the development of cancer. (3) MicroRNA is the most valuable part in regulating gene expression. We performed the bio-information searching about SNPs within microRNA binding site of inflammatory cytokines, aims at providing referenes for future systematic investigation of the association between this group of bio-marker and susceptibility of gastric cancer.MethodAll the Chinese and English literatures about the association H. pylori eradication therapy and gastric cancer susceptibility were searched during 1997.01-2010.10. We screened all literatures and retrieved data related through certain into exclusion standard according to the standard beforehand. The analyses were conducted with the Review Manager (RevMan, version 5.0.24.0) and Stata 10.0(version 10.0, Statacrop LP). We estimated the pooled relative risk (RR) and its 95% confidence interval (95%CI). And relative risk reduction(RRR) was used to estimate clinical effect of H. pylori eradication therapy.This study choosed traditional case-control study of epidemiology combined with familial comparative study in Henan province. We interviewed every inhabitant for the occurrence of gastric cancer in their families and collected their venous blood. The inflammatory cytokine genome DNA polymorphisms genotypes were detected. H. pylori infection through ELISA was examined. Then we compared their distribution difference between the case and control families.We selected databases "Patrocles" for searching of SNPs within microRNA binding sites related inflammatory cytokine. According to the criteria setted before seaching about the type of seed region and the limits of Population frequene, we screened for the high-frequeney SNPs among Chinese Population within microRNA binding sites of inflammatory genes.Results1. The study was consisted of 13 reseaches including four (33.8%) randomized controlled trails (RCTs) and nine (66.2%) non-randomized controlled trails(n-RCTs). It had no showed any publication bias and significant heterogeneity in all literatures included in meta-analysis. The overall analysis showed H. pylori eradication therapy was associated with reduced risk of gastric cancer (RR=0.51,95% CI:0.40-0.65, Z= 5.37, P<0.01,). In subgroup analyses, H. pylori eradication therapy reduced the risk for the incidence of gastric cancer in both RCTs and non-RCTs. The effect was significant in dyspeptic patients but not in general population.2. Most of polymorphisms genotypes of inflammatory cytokine were associated with increased risk of non-cardiac adenocarcinoma of stomach but IL-1B-31 and TNF-A-238. The frequency distribution of dangerous genotypes was signifant different between the case and control families, which OR values was higher in the fitst degree relatives, comparing the second degree relatives. The strength reduced along with the relative degree decreasing. But parts of genotypes had no frequency distribution differences. The positive H. pylori status could increase the risk of gastric cancer and the risk reduced along with the relative degree decreasing.3. In total, we screened 54 genes related inflammatory. We found 338 within microRNA binding sites from the Patrocles database in the initial searching. And 296 were validated SNPs. Through searching of the dbSNP database and calculating Gibbs free energy, we found 10 SNPs with a high frequeney among Chinese Population.Conclusions1. H. pylori eradication therapy reduces the incidence gastric cancer, especially for dyspeptic patients. These findings support that H. pylori eradication therapy is beneficial in preventing gastric cancer.2. H. pylori infection could increase the risk of gastric cancer. The variant genotypes of inflammatory genes are the risk factors of gastric cancer.3. The searching for the high-frequeney SNPs within microRNA binding sites related inflammatory cytokine among Chinese Population will be useful for the future molecular mechanism studies of gastric cancer.