| Objective:Gastric cancer is a kind of malignant tumor with high ability of proliferation and invasivity.in China,the morbidity and mortality of gastric cancer are second only to lung cancer.At present,the treatment for gastric cancer is very limited,resulting in a five-year survival rate of less than 20%.In the previous study,we integrated and analyzed the micro RNA and m RNA microarray data,found that miR-125 b was highly expressed in gastric cancer and was associated with poor prognosis of gastric cancer patients.There is a significant gender difference in the incidence of gastric cancer(the average male-to-female ratio is 2:1),but there is a significant increase in the incidence of gastric cancer in women under the age of 40(1.4:1).In the previous study,we integrated and analyzed several gastric cancer data sets,and the preliminary analysis results confirmed that the gender difference may be related to androgen receptor AR.Therefore,in this study,we explore the mechanism of miR125 b and AR in the occurrence and development of gastric cancer and look for potential therapeutic targets for gastric cancer.Method:In the first part,we explore the mechanism of miR-125 b in gastric cancer through clinical sample data analysis and experimental verification.In the second part,we explore the role and molecular mechanism of AR/miR-125 b pathway in prognosis and targeted therapy of gastric cancer through association analysis,mechanism study and transformation study.Result:Part one: the molecular mechanism of miR-125 b involved in malignant progression of gastric cancer.the expression of miR-125 b in gastric cancer showed that the expression of miR-125 b was significantly up-regulated in tumor tissues.Survival analysis showed that miR-125 b was associated with poor prognosis.Signal pathway analysis showed that 178 genes negatively related to miR-125 b expression were mainly involved in apoptosis pathway.In vivo and in vitro experiments confirmed that miR-125 b inhibited cell apoptosis.Mechanism experiments confirmed that apoptotic genes BIK and CASP6 were the targets of miR-125 b.Part two: AR/miR-125 b pathway can be used as a molecular marker for prognosis and targeted therapy of female gastric cancer.In association analysis,we confirmed that the genes with significant gender differences in gastric cancer were mainly enriched on the X chromosome,and the inactivation and escape of X chromosome,prostate cancer-related pathway and hormone synthesis pathway in the main pathways of the differential genes were all related to AR.Survival analysis showed that the survival time of patients with high expression of AR was shorter,and there was a significant correlation between the prognosis of female patients and the expression of AR.The results of cluster analysis confirmed that there was a positive correlation between AR and miR-125 b expression.Mechanism research: bioinformatics prediction results show that miR-125 b promoter contains four ARE;Ch IP,EMSA and Luciferase experiments confirmed that AR can transcriptively activate miR-125 b,and transcriptional activation is regulated by androgens.In the part of transformation study,anti-androgen therapy inhibited the viability of AR-positive gastric cancer cells and promoted apoptosis;in vivo,bicalutamide significantly inhibited the growth of transplanted tumor in female mice and promoted necrosis and apoptosis,but in male mice,bicalutamide only inhibited the growth of transplanted gastric cancer with high expression of AR,but had no inhibitory effect on the growth of transplanted tumor with low expression of AR.Conclusion:miR-125 b inhibits apoptosis signal pathways of gastric cancer by targeting proapoptotic genes Casp6 and BIK,resulting in a poor prognosis of female patients with gastric cancer;AR transcriptively activate the expression of miR-125 b in gastric cancer,and blocking the AR / miR-125 b signaling pathway can significantly inhibit the expression of miR-125 b and induce apoptosis of gastric cancer cells.So anti-androgen therapy can be used for AR-positive gastric cancer. |
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