Expression and Prognostic Significance of PDIA3 in Cervical Cancer

Abstract

To investigate the expression of protein disulfide isomerase A3 (PDIA3/ERP57) in cervical cancer and its clinical prognostic significance as well as its function and possible action mechanism in the progression of cervical cancer. Based on TIMER2.0 database, the human protein map (Human Protein Atlas) was used to determine the expression level of PDIA3 protein for the analysis of PDIA3 expression in 39 The Cancer Genome Atlas (TCGA) tumors. The PDIA3 expression in cervical cancer tissues in the TCGA and Genotype-Tissue Expression databases was further verified based on the GEPIA2 database to analyze the relationship between the PDIA3 expression and the pathological stage of cervical cancer patients. Immunohistochemistry was used to detect the PDIA3 expression in cervical cancer tissue microarray, including 111 cancer tissue samples and 24 adjacent cancer tissue samples, and the relationship between PDIA3 protein expression and clinical characteristics of patients with cervical cancer was analyzed. The Kaplan–Meier method and log-rank test were used for survival analysis. Based on the cBioPortal database, the Spearman’s and Pearson’s methods were used to analyze the correlation between PDIA3 expression and DNA methylation. The correlation between PDIA3 expression and the infiltration levels of each immune cell in cervical cancer was evaluated. The STRING was used to construct protein interaction network. Based on LinkedOmics database, the Spearman’s method was used to analyze the co-expressed genes of PDIA3 in TCGA cervical cancer. The gene ontology functional enrichment analysis was performed on Top 50 differentially co-expressed genes based on DAVID database. The PDIA3 expression in cervical cancer tissues was significantly higher than that in normal tissues, which ( F = 2.74 , PR (>F) = 0.0436) was significantly increased with the progression of tumor stage, and PDIA3 showed strong immunoreactivity in cervical cancer tissues. In cervical cancer patients, overall survival ( P = 0.014 ), disease-specific survival ( P = 0.013 ), disease-free interval ( P = 0.023 ), and progression-free interval ( P = 0.001 ) in those with high expression of PDIA3 were significantly lower than those with low expression, suggesting that high expression of PDIA3 was associated with poor prognosis. In cervical cancer, high expression of PDIA3 was associated with DNA methylation and negatively correlated with B cell memory ( r = − 0.132 , P = 0.021 ), T cell regulatory ( r = − 0.127 , P = 0.026 ), monocytes ( r = − 0.204 , P = 0 ), and macrophages M2 ( r = − 0.142 , P = 0.013 ), whereas positively correlated with levels of NK cell activated ( r = 0.162 , P = 0.005 ) and mast cells activated ( r = 0.119 , P = 0.037 ). The genes positively correlated with PDIA3 expression included HSPA5 and PPIB, which were mainly enriched in biological processes, such as endoplasmic reticulum (ER) protein folding and ER stress response. PDIA3 can be used as a marker of poor prognosis of cervical cancer. The expression level of PDIA3 is closely related to the survival and prognosis of cervical cancer patients, DNA methylation, and immune cell infiltration.

Clinicopathological significance of protein disulphide isomerase A3 and phosphorylated signal transducer and activator of transcription 3 in cervical carcinoma

“…Furthermore, patients with high PDIA3 expression showed significantly lower DFS and OS rates than patients with low expression. Our results are in line with Zhang et al [18], who found that PDIA3 was highly expressed in 60.4% and was significantly higher than that in normal tissue (p < 0.05) and showing strong correlation with pathological type, progression of tumour stage, lower OS, and DFS, suggesting that high expression of PDIA3 can be used as an indicator of poor prognosis of cervical carcinoma.…”

“…The cytoplasmic PDIA3 expression was scored according to the percentage of positive cells, into 0 for ≤ 5%, 1: 6-30%, 2: 31-80%, and 3: > 80%. The intensity scored 1-3 and the final score ranged from 0 to 9, considered as low (0-2) or high expression (3-9) [18].…”

The role of PDIA3 in oral squamous cell carcinoma and its value as A diagnostic and prognostic biomarker

“…In hepatocellular carcinoma, increased expression of PDIA3 is associated with poor prognosis [ 9 ]. PDIA3 is also up-regulated in cervical cancer tissues, and elevated expression of PDIA3 is associated with shorter survival of patients, suggesting that PDIA3 can be used as a marker of poor prognosis in cervical cancer [ 30 ]. Together, these currently available studies indicate that PDIA3 is associated with a shorter survival time in cancer patients and may be used as a biomarker for poor prognosis in cancer patients.…”

“…For example, Zhang et al reported that PDIA3 correlated with the infiltration of macrophages and T cells and was involved in the suppression of anti-tumor immunity in gliomas [ 37 ]. In another study, PDIA3 expression was found to be negatively correlated with infiltration of B cell memory, T cell regulatory, monocytes, and macrophages M2, but positively correlated with NK cell activated and mast cells activated in cervical cancer [ 30 ]. PDIA3's impact on immune cell infiltration in cancer is complex and context-dependent.…”

PDIA3 driven STAT3/PD-1 signaling promotes M2 TAM polarization and aggravates colorectal cancer progression

“…Its primary locus of activity is situated within the endoplasmic reticulum (ER), though it also garners a presence within cellular membranes and in the extracellular matrix [ 9 , 10 ]. PDIA3’s relationship with cancerous transformation and progression are both intimate and insidious, with heightened expression levels detected in a gamut of malignancies, including diffuse glioma [ 11 ], clear cell renal cell carcinoma [ 12 ], hepatocellular carcinoma (HCC) [ 13 ], breast cancer [ 14 ], cervical cancer [ 15 ], and gastric cancer [ 16 ], an overexpression which traditionally signals a grim prognosis. In glioblastoma cellular models, PDIA3 has shown a suppressive impact on M2 macrophage polarization and pro-inflammatory cytokine synthesis [ 17 ].…”