| Background:Prostate cancer ranks high in the incidence and mortality of male malignant tumors in the world.Besides surgery,prostate cancer treatment needs to be combined with more adjuvant therapies to improve the benefit of tumor treatment.Metformin is considered to have antitumor effects on a variety of cancers.However,different cancers respond differently to metformin,and there is no consensus on the effect of metformin on prostate cancer.Furthermore,long-term use of metformin will also lead to the occurrence of drug resistance,affecting the long-term effect of treatment.Therefore,a study is necessary to further understand the specific mechanism of metformin anti-tumor action,seek more therapeutic targets,and provide sensitive drug treatment strategies.Materials:1.Prostate cancer and Metformin were searched in Wanfang,CNKI,Pubmed,Embase and other databases with Chinese and English search terms.The retrieval period was from the establishment of the database to December 31,2021.2.The second part of the research involved the GSE83673 dataset of GEO database.Clinical cohort study included MGH follow-up cohort and TCGA cohort.3.Prostate cancer and adjacent benign frozen tissues were collected in the First Affiliated Hospital of Guangzhou Medical University.Human Pca TMA was purchased from Xi ’an Ailina Biotechnology Co.,LTD.Two types of human PCa cell(PC3 and DU 145)were purchased from ATCC.Methods:1.Meta-analysis was adopted to update systematic evaluation and analyze the benefit of metformin on prognosis of prostate cancer patients.2.The effect of metformin on the immunophenotype and immune status of prostate cancer cells was evaluated by immune microenvironment infiltration analysis on the gene expression dataset of GSE83673.A BCR-related module was identified in the MGH clinical cohort by WGCNA.An IRG-related signature was constructed by using random forest and multivariate stepwise Cox regression analysis.The immunophenotype and immune status of stratified prostate cancer patients with IRG-related signature were evaluated by TIMER database analysis and CIBERSORT algorithm.Kaplan-meier curve was used to evaluate the relationship between different immune risk stratification and prognosis of prostate cancer.3.Genome-wide CRISPR-Cas9 transcriptional activation screening and deep sequencing analysis were used to screen metformin(MET)resistance genes in prostate cancer cells.Candidate MET resistance genes were overexpressed and their resistance to metformin was verified by CCK8.The relationship between candidate MET resistance genes and prognosis of prostate cancer were analyzed by Kaplan-meier method and log-rank test.Immunohistochemistry confirmed the difference of RAD9A expression between prostate cancer and normal prostate tissue.CIBERSORT algorithm was used to evaluate the effects of RAD9A on the immunophenotype and immune status of prostate cancer patients.Result:1.Metformin reduces the risk of BCR and specific mortality in prostate cancer.2.Metformin can change the immune microenvironment and immune status of prostate cancer cells;The immune status of prostate cancer patients is closely related to clinical prognosis.3.Six candidate MET resistance genes including ECE1,ABCA12,BPY2,EEF1A1,RAD9A and NIPSNAP1 were screened from prostate cancer cells and showed resistance to metformin.In addition,RAD9A may down-regulate HLA I expression and up-regulate regulatory T cells,counteracting the antitumor effect of metformin.Conclusion:1.Metformin benefits the prognosis of prostate cancer patients to a certain extent,but the conclusions above still need to be further confirmed by more researches.2.The regulation mechanism of metformin against prostate cancer was possibly realized by changing tumor immune microenvironment and immune cell phenotype and improving tumor immune state.3.The metformin resistance genes screened in this research contribute to selecting a more suitable population for the adjuvant treatment of metformin in prostate cancer,providing sensitization strategies and new therapeutic targets. |
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