Pan-Cancer Analysis of PDIA3: Identifying It as a Potential Biomarker for Tumor Prognosis and Immunotherapy

Abstract

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 plays an important role in the occurrence and development of many tumors, there is no systematic pan-cancer study on PDIA3. Therefore, in this study, the differential expression of PDIA3 in 33 kinds of tumors was analyzed to explore its ability to regulate tumor immunity as a biomarker and evaluate its role in different cancer onset stages or clinical prognosis. In this paper, by analyzing the multilevel data including 33 kinds of cancers in the databases of Cancer Genome Atlas (TCGA), UCSC Xena, Cancer Cell Encyclopedia (CCLE), Genotypic Tissue Expression (GTEx), Human Protein Atlas (HPA), cBioPortal, and GDC; the differential expression level of PDIA3 in different types of malignant tumors and its relationship with prognosis and the potential correlation between PDIA3 expression and microsatellite instability (MSI), tumor mutation load (TMB), mismatch repair gene (MMR), DNA methylation level, and immune infiltration level were analyzed with bioinformatics. The results showed that PDIA3 was highly expressed in 19 types of cancers, but downregulated only in THCA. Next, PDIA3 in different tumors was positively or negatively correlated with patient outcome, Kaplan-Meier survival analysis showed that PDIA3 plays an important role in the prognosis of patients with KIRP, KICH, and CESC and may be used as a prognostic biomarker, and the methylation level of PDIA3 promoter region was closely related to patient outcome in eight tumors. The expression level of PDIA3 was correlated with TMB in 13 tumors and MSI in 9 tumors. Among them, 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. In addition, the expression of PDIA3 in eight kinds of tumors, including BRCA, HNSC, THYM, LGG, LUAD, LUSC, PRAD, and THCA, had the highest correlation with the infiltration degree of immune cells, and the expression of PDIA3 had the highest correlation with the infiltration degree of 11 kinds of immune cells, including regulatory T cell and macrophages. And LGG is the tumor most likely to be affected by the tumor microenvironment to affect its development and prognosis. To sum up, 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 and can be used as a prognostic biomarker for these tumors.