Clinical Application Value Of PRDX Gene Family In Brain Glioma And Exploration Of The Mechanism Of PRDX

Part Ⅰ The Expression and Prognostic Value of PRDX Family in Glioma.Objective: PRDX family is a family of antioxidant enzymes,which has been proved to be involved in and regulate the occurrence and development of many kinds of tumors.However,its expression and prognostic value in gliomas are not clear.In this study,multiple databases were used to explore the expression and prognostic value of PRDX gene family in gliomas.Methods: The m RNA expression data and clinical information of malignant gliomas were analyzed by downloading CGGA,TCGA,Gravendeel and REMBRANDT databases,and the expression of PRDX gene in normal brain tissue and tumor tissue was compared by t test.Kaplan-Meier survival curve and log-rank test were used to evaluate the difference of overall survival time(OS)between high and low expression groups of PRDX family members;univariate and multivariate Cox regression analysis was used to determine independent prognostic factors.The CGGA dataset was used as the training group to construct a line chart(Nomogram)prognostic model for predicting the overall survival rate of glioma 1 at 3 and 5 years,and the TCGA and Gravendeel data were used as the verification group for external verification.Results: The m RNA expression levels of PRDX family members in normal brain tissue and tumor tissue were compared by CGGA and REMBRANDT data sets.The results showed that the expression of PRDX4 in glioma tissue was significantly higher than that in normal brain tissue,while the expression of PRDX5 in tumor tissue was significantly decreased.Kaplan-Meier survival analysis showed that the clinical prognosis of glioma patients with high expression of PRDX1,PRDX4 and PRDX6 was worse than that of patients with low expression.On the contrary,the overall survival time of patients with high expression of PRDX5 was longer than that of patients with high expression of PRDX5,while the results of PRDX2 and PRDX3 were inconsistent in all data sets.In CGGA dataset,the results of univariate and multivariate Cox regression analysis showed that the expression of PRDX1,PRDX4 and PRDX5 were independent prognostic factors of glioma.Secondly,the expression of PRDX4 and PRDX5 was correlated with high and low grade of glioma,IDH state and1p19 q co-deletion state,respectively.Taking the CGGA data set as the training group,the Nomogram prognosis model combined with the expression of PRDX4,PRDX5 and common clinicopathological parameters was constructed,and the external verification was carried out by C-index,time-dependent ROC curve and calibration curve in the training group and verification group.The results showed that the Nomogram model had high accuracy in predicting the 1-,3-and 5-year survival rate of glioma patients.Conclusion: These results suggest that PRDX4 and PRDX5 may be potential diagnostic and prognostic markers of gliomas,and the Nomogram prognostic model constructed by combining the m RNA expression of PRDX4 and PRDX5 and clinicopathological features has a certain application value.Part Ⅱ The Prognostic Analysis of PRDX4 and PRDX5 Protein Expression in Glioma and A Nomogram Developed to Predict The Prognosis of GliomaObjective: To explore and verify the prognostic value of PRDX4 and PRDX5 protein expression in gliomas through a single center cohort,and to analyze the independent factors affecting prognosis,and to construct a Nomogram model for predicting 1-,3-and 5-year survival rates of glioma patients and evaluate them internally,in order to provide ideas for clinical individualized treatment.Methods: The clinical data of 136 patients with newly diagnosed gliomas who underwent craniotomy in the Department of Neurosurgery of the affiliated Cancer Hospital of Guangxi Medical University from January 2013 to December 2018 were analyzed retrospectively.the expression levels of PRDX4 and PRDX5 in gliomas were detected by immunohistochemistry,and the correlation between them and clinicopathological features was analyzed by chi-square test.The difference of OS between high and low expression groups of PRDX4 and PRDX5 was evaluated by Kaplan-Meier survival curve and logrank test.Then,combined with the clinicopathological characteristics of glioma patients,the independent factors affecting the prognosis of glioma patients were identified by univariate and multivariate Cox regression analysis,and the Nomogram model for predicting the 1-,3-and 5-year survival rate of glioma patients was constructed and evaluated internally.The accuracy of the model was evaluated by C-index and calibration curve,and the differentiation of the model was evaluated by time-dependent ROC.Results: High expression of PRDX4 protein was significantly correlated with higher pathological WHO grade,Ki67 expression rate and survival status.OS was significantly shortened in patients with high expression of PRDX4 protein(P < 0.001).Multivariate Cox regression analysis showed that high expression of PRDX4 protein(HR=1.83;95% CI,1.10-3.03;P=0.019)was an independent factor for poor prognosis,but there was no significant correlation between PRDX5 protein and clinicopathological features.The difference between high and low expression OS of PRDX5 was not statistically significant in either Kaplan-Meier survival analysis or Cox proportional hazard model univariate survival analysis.A glioma prognostic model was constructed by combining the expression of PRDX4 protein with other independent clinicopathological prognostic factors,and it was found that the expression of PRDX4 could increase the C-index to 0.738.The AUC values for predicting 1-,3-and 5-year survival rates in this cohort were 0.739,0.860 and 0.834,respectively,which were higher than those of independent prognostic factors.The calibration curve showed that the predicted results of the model were highly consistent with the actual observation results.In addition,it was confirmed that the Nomogram model could effectively stratify the risk of patients,and there was a significant difference in prognosis among the three groups(P < 0.001).Conclusion: In this study,PRDX4 may be a potential prognostic marker of glioma at the protein expression level,and it is confirmed that the Nomogram model combined with PRDX4 expression and clinicopathological features can accurately predict the prognosis of glioma patients.Part Ⅲ Exploring The Potential Mechanism of PRDX4 in Glioma Based on Genome-Wide DataObjective: The part I and II of the study screened the prognosis-related PRDX4 gene in gliomas,then we used bioinformatics methods to explore its potential biological function in gliomas.Methods: Firstly,Pearson correlation analysis was carried out between the whole genome expression profile data and PRDX4 genes in CGGA,TCGA,Gravendeel and REMBRANDT datasets,respectively,and the co-expressed genes of PRDX4 in each dataset were screened.The results of the last four data sets were considered to be the most accurate co-expressed genes,and then the GO function and KEGG pathway enrichment of these genes were analyzed by R software cluster Profiler package.According to the median value of PRDX4,the whole CGGA genome data were divided into high and low expression groups,and single gene GSEA analysis was carried out,then c5(GO gene set)and c2(KEGG gene set)were downloaded from GSEA website,and gene set mutation analysis(GSVA)algorithm was used to verify the results of the above two steps.In addition,Pearson correlation analysis was used to study the relationship between PRDX4 and the expression of a variety of oncogenes in CGGA datasets,including cell cycle and proliferation related genes,angiogenic related genes,therapeutic drug resistance / resistance related genes,and migration and invasion related genes.Finally,CGGA data were collected to collect the patients with primary glioma who received radiotherapy or chemotherapy and the most malignant GBM subgroup for Kaplan-Meier survival analysis to explore the prognostic value of PRDX4 expression in patients who had received radiotherapy or chemotherapy.Results: A total of 862 overlapping genes were found in 4 data sets.The results of GO function and KEGG pathway enrichment of co-expressed genes and GSEA results showed that PRDX4 was mainly involved in biological processes such as biological adhesion,cell proliferation,cell migration,promoting angiogenesis and epithelial stromal EMT,and the results of GSVA were consistent with the above results.In addition,it was found that PRDX4 was positively correlated with the expression of many oncogenes.Kaplan-Meier survival analysis was performed in patients with primary gliomas who had received radiotherapy or chemotherapy and primary GBM subgroups.the results showed that the prognosis of patients with high expression of PRDX4 was worse than that of patients with low expression of PRDX4 in all groups.Conclusion: The analysis of bioinformatics function reveals that PRDX4 may be related to glioma cell proliferation,migration,EMT and angiogenic biological process,and the expression of PRDX4 may be related to the survival benefit of patients receiving radiotherapy and chemotherapy.The results of this study provide ideas for the study of the mechanism of PRDX4 in glioma.