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. 2022 Nov 11:2022:4382645.
doi: 10.1155/2022/4382645. eCollection 2022.

Expression and Prognostic Significance of PDIA3 in Cervical Cancer

Jing Zhang #  1 , Hui Li #  2 , Huling Li  1 , Dandan Lin  1 , Xiaoyan Wang  1 , Kai Wang  3
Affiliations

Expression and Prognostic Significance of PDIA3 in Cervical Cancer

Jing Zhang et al. Int J Genomics. .

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.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Expression of PDIA3 in various TCGA tumor tissues (∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001).
Figure 2
Figure 2
Protein expression levels of PDIA3 in various HPA tumor tissues.
Figure 3
Figure 3
(a) Expression of PDIA3 gene in normal tissue and tumor tissue. (b) Relationship between PDIA3 expression and tumor staging.
Figure 4
Figure 4
Expression of PDIA3 in cervical cancer and adjacent cancer tissues (IHC 200×). (a) and (b) The positive expression of PDIA3 protein in cervical cancer samples. (c) and (d) The negative expression of PDIA3 protein in normal tissue samples.
Figure 5
Figure 5
(a) Relationship between PDIA3 expression and overall survival (OS). (b) Relationship between PDIA3 expression and disease-specific survival (DSS). (c) Relationship between PDIA3 expression and disease-free interval (DFI). (d) Relationship between PDIA3 expression and progression-free interval (PFI).
Figure 6
Figure 6
Correlation between PDIA3 expression and DNA methylation.
Figure 7
Figure 7
(a) Relationship between the PDIA3 expression and B cell memory in cervical cancer. (b) Relationship between the PDIA3 expression and T cell regulatory in cervical cancer. (c) Relationship between the PDIA3 expression and monocytes in cervical cancer. (d) Relationship between the PDIA3 expression and macrophages M2 in cervical cancer. (e) Relationship between the PDIA3 expression and NK cell activated in cervical cancer. (f) Relationship between the PDIA3 expression and mast cells activated in cervical cancer.
Figure 8
Figure 8
(a) Construction of PPI protein interaction network of PDIA3 gene. (b)–(k) Correlation between related genes and PDIA3 expression [(b): PPIB. (c): HSP90B1. (d): P4HB. (e): PDIA4. (f): HYOU1. (g): PDIA6. (h): MANF. (i): CRELD2. (j): HSPA5. (k): MYDGF (C19ORF10)]. (l) The expression of 10 target genes in each tumor.
Figure 9
Figure 9
(a) PDIA3 differentially co-expressed top 50 positive related genes in cervical cancer. (b) PDIA3 differentially co-expressed top 50 negative related genes in cervical cancer.
Figure 10
Figure 10
KEGG bubble plot of PDIA3 differentially co-expressed top 50 genes.
Figure 11
Figure 11
KEGG pathway of PDIA3 differentially co-expressed genes.
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