Effect Of Esomeprazole On AKT/FOXO3a Pathway In Gastric Cancer Cells And Gene Expression Profile Analysis

Background and objectiveGastric cancer is one of the most common malignant tumors in the digestive system.According to WHO statistics,China is still one of the countries with the highest incidence of gastric cancer in the world.At present,there is no standard treatment for advanced gastric cancer,and the prospect of gastric cancer chemotherapy is not optimistic.Exploring other disease treatment drugs for anti-tumor treatment is a relatively intelligent drug development method,and gradually formed a hot research method,proton pump inhibitors is one of them.In the previous studies of the research group,it was found that esomeprazole can significantly inhibit the growth of human gastric cancer AGS cells and enhance the sensitivity of chemotherapeutic drugs in vitro.Therefore,this study is to investigate the effect of esomeprazole on human gastric SGC-7901 and AGS cells.The influence of signal pathway in cells and the effect of esomeprazole on the gene expression profile of human gastric cancer AGS cells,revealing the molecular mechanism of esomeprazole on human gastric cancer cells,and providing experimental theoretical basis for further exploring the clinical application of the anti-tumor drug.MethodsCCK-8 method was used to detect the inhibitory effect of esomeprazole on the proliferation of gastric cancer SGC-7901 cells.The expression of AKT?FOXO3a and related proteins in SGC-7901 cells and AGS cells was detected by Western Blot.The effect of esomeprazole on the gene expression profile on human gastric cancer AGS cells was studied using Agilent gene expression profile chip.After processing AGS cells,total RNA was extracted,followed by gene chip hybridization,and data processing and analysis were performed.Six differentially expressed genes were verified by RT-PCR.Go analysis and Pathway analysis for functional prediction of differential genes.Results1.Different concentrations of esomprazole treated on human gastric cancer SGC-7901 cells for 48 hours.With the increase of drug concentration,the profileration inhibition rate of cells increased gradually,the difference was statistically significant.2.After treated with different concentrations of esomprazole for 48 hours in SGC-7901 cells,the expression of AKT,caspase 3 and caspase7 were down-regulated and the expression of EGFR and FOXO3 a were increased with increasing concentration in a certain concentration range,the difference was statistically significant.3.When esomprazole combined with EGFR inhibitor AG1478 were applied to SGC-7901 cells,the expression of EGFR and AKT decreased,and the expression of FOXO3 a,caspase3,Bcl-2 and E-cadherin increased,the difference was statistically significant.4.When esomprazole conbined with EGFR inhibitor AG1478 were applied to AGS cells,the expression of EGFR and AKT decreased,and the expression of FOXO3 a,caspase3,caspase7,Bcl-2,ATP4 B and E-cadherin increased.5.By compating the gene expressed profiles of AGS cells before and after esomeprazole,a total of 948 differentially expressed lncRNAs,1,197 mRNAs,114 circRNAs,and 520 Multiple-complexes were detected.6.Three lncRNAs and three mRNAs were randomly selected from differentially expressed lncRNAs and mRNAs for RT-PCR verification.The results of verification were consistent with the result of gene profiles.7.GO analysis of differentially expressed genes in the control group and the esomeprazole drug-treated showed that DNA replication was mainly involved in biological process,nucleosome in the cellular component,and protein heterodimerization activity in molecular function.8.Pathway predictive analysis of differentially expressed genes showed significant differences in EGFR-TKI resistance,FOXO signaling pathway,platinum resistance and autophagy.Conclusion1.Esomprazole inhibited the profileration of human gastric cancer SGC-7901 cells in a concentration-dependent manner by AKT/FOXO3 a signaling pathway,and the EGFR-TKI resistance signaling pathway is activated.The mechanism needs further study.2.Esomeprazole can affect the expression of lncRNA,circRNA and mRNA in gastric cancer AGS cells;Its biological effects may be related to the regulation of FOXO,EGFR-TKI resistance,platinum resistance and autophagy.