| Objective: Protein disulfide isomerase A3(PDIA3)is a kind of thiol oxidoreductase with a wide range of functions,and its expression is elevated in a variety of tumors,which is closely related to the invasion and metastasis of tumor cells,and has a significant impact on the immunogenicity of tumor cells.Although more and more studies have shown that PDIA3 can regulate the progression of many kinds of cancer,it is still unclear to carry out systematic pan-cancer research on PDIA3 and its role in immunotherapy of cervical cancer and lung adenocarcinoma.Therefore,this study aims to analyze the differential expression of PDIA3 in cervical cancer,lung adenocarcinoma and pan-cancer,evaluate its clinical prognostic significance and possible mechanism of action in different cancers,and explore its ability to regulate tumor immunity as a biomarker.Methods: This study was performed by downloading multi-level data containing 33 cancers from The Cancer Genome Atlas(TCGA),UCSC Xena,Cancer Cell Lineage Encyclopedia(CCLE),Genotype Tissue Expression(GTEx),and GDC.R software was used to conduct log2 standardization on gene expression data.The Wilcoxon rank sum test was used to compare the differential expression of PDIA3 gene between cancer and adjacent tissue samples in different tumors.The survival prognosis was analyzed by Kaplan-Meier method,log-rank test and Cox proportional risk regression model.Correlation analysis between the two variables was performed using Spearman’s test or Pearson’s test.At the same time,111 cases of cervical cancer tissue and 24 cases of paracancerous tissue samples containing clinical characteristics were collected for immunohistochemical test verification,and several online websites such as TIMER2.0,GEPIA2,c Bio Portal,Linked Omics and DAVID were used.Bioinformatics methods were applied to analyze the differential expression levels of PDIA3 in pan-cancer and its clinical prognostic significance.Based on the pan-cancer study,the differential expression profile,survival prognostic value and clinical significance of PDIA3 in cervical cancer and lung adenocarcinoma were further explored.Results: The analysis results of PDIA3 gene in pan-cancer showed that:(1)PDIA3 was highly expressed in 19 types of cancers,but down-regulated only in THCA.(2)The results of TCGA and HPA analysis were consistent.PDIA3 showed moderate staining in normal thyroid tissue and weak staining in tumor tissue.(3)The expression level of PDIA3 in THYM has the strongest correlation with TMB,and the expression level of PDIA3 in READ has the strongest correlation with MSI.(4)In addition,the expression of PDIA3 in eight kinds of tumors,including BRCA,THYM,LGG,and LGG is the tumor most likely to be affected by the tumor microenvironment to affect its development and prognosis.(5)The methylation level of PDIA3 promoter region was closely related to patient outcome in eight tumors.(6)PDIA3may affect the tumorigenesis and pathological process by affecting cell adhesion,protein synthesis and immune function.The analysis results of PDIA3 gene in cervical cancer showed that:(1)The expression of PDIA3 in cervical cancer is higher than that in normal tissues,which was significantly increased with the progression of tumor stage,and PDIA3 showed strong immunoreactivity in cervical cancer tissues.(2)The high expression of PDIA3 gene is associated with poor prognosis in patients with cervical cancer.(3)In cervical cancer,high expression of PDIA3 gene was associated with DNA methylation and it may regulate the progression of cervical cancer by affecting the six most critical immune cell types.(4)The genes positively correlated with PDIA3 expression included HSPA5,PPIB,and HSP90B1,which were mainly enriched in biological processes such as endoplasmic reticulum protein folding,endoplasmic reticulum stress response.The analysis results of PDIA3 gene in lung adenocarcinoma showed that:(1)In the TCGA database,PDIA3 showed high expression in 15 cancer types,with down-regulated expression only in THCA.Combined TCGA and GTEx database analysis revealed significant differences in PDIA3 expression in 25 tumor types.(2)PDIA3 expression was higher in lung adenocarcinoma tissues than in normal tissues,and PDIA3 showed moderate staining in normal lung tissues and strong staining in tumor tissues.(3)High expression of PDIA3 gene is associated with poor prognosis of LUAD.(4)PDIA3 expression in lung adenocarcinoma was most correlated with the level of 15 immune cell infiltration and was significantly negatively correlated with the immune score and stromal score.(5)In TIMER,after adjustment for tumor purity,PDIA3 expression levels were significantly correlated with 21 of the 33 immune cell markers in LUAD and significantly positively correlated with immune checkpoint expression.Conclusion: This study suggests that PDIA3 plays an important role in the occurrence and development of KIRP,KICH,and CESC and in the immunotherapeutic response of THYM,READ,and LGG.The expression level of PDIA3 was closely related to the survival prognosis,DNA methylation and immune cell infiltration of patients with cervical cancer.High expression of PDIA3 is associated with adverse clinical outcomes in lung adenocarcinoma patients.PDIA3 may affect lung adenocarcinoma development by regulating tumor infiltrating cells in TME,and PDIA3 can be used as a prognostic biomarker for these tumors. |
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