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. 2018 Feb;39(2):501-510.
doi: 10.3892/or.2017.6134. Epub 2017 Dec 4.

P4HB and PDIA3 are associated with tumor progression and therapeutic outcome of diffuse gliomas

Hecun Zou  1 , Chunjie Wen  1 , Zhigang Peng  2 , Ying-Υing Shao  1 , Lei Hu  3 , Shuang Li  3 , Cuilin Li  3 , Hong-Hao Zhou  1
Affiliations

P4HB and PDIA3 are associated with tumor progression and therapeutic outcome of diffuse gliomas

Hecun Zou et al. Oncol Rep. 2018 Feb.

Abstract

Diffuse gliomas are the most common type of primary brain and central nervous system (CNS) tumors. Protein disulfide isomerases (PDIs) such as P4HB and PDIA3 act as molecular chaperones for reconstructing misfolded proteins, and are involved in endoplasmic reticulum stress and the unfolded protein response. The present study focused on the role of P4HB and PDIA3 in diffuse gliomas. Analysis of GEO and HPA data revealed that the expression levels of P4HB and PDIA3 were upregulated in glioma datasets. their increased expression was then validated in 99 glioma specimens compared with 11 non-tumor tissues. High expression of P4HB and PDIA3 was significantly correlated with high Ki-67 and a high frequency of the TP53 mutation. Kaplan-Meier survival curve and Cox regression analyses showed that glioma patients with high P4HB and PDIA3 expression had a poor survival outcome, P4HB and PDIA3 could be independent prognostic biomarkers for diffuse gliomas. In vitro, knockdown of PDIA3 suppressed cell proliferation, induced cell apoptosis, and decreased the migration of glioma cells. Furthermore, downregulation of P4HB and PDIA3 may contribute to improve the survival of patients who receive chemotherapy and radiotherapy. The data suggest that high expression of P4HB and PDIA3 plays an important role in glioma progression, and could predict the survival outcome and therapeutic response of glioma patients. Therefore, protein disulfide isomerases may be explored as prognostic biomarkers and therapeutic targets for diffuse gliomas.

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Figures

Figure 1.
Figure 1.
Expression of P4HB and PDIA3 in glioma samples of the GSE4290 dataset.
Figure 2.
Figure 2.
Representative immunohistochemistry images of P4HB (A) and PDIA3 (B) protein in normal brain tissues, low-grade glioma and glioblastoma tissues.
Figure 3.
Figure 3.
Kaplan-Meier survival curve analysis with a log-rank comparison according to P4HB and PDIA3 expression in glioma samples of TCGA (A) and GEO datasets [GSE4271 (B), GSE4412 (C), and GSE43378 (D)].
Figure 4.
Figure 4.
qRT-PCR analysis of relative P4HB and PDIA3 expression in 99 diffuse glioma specimens and 11 non-tumor brain tissues (NC). *P<0.05, **P<0.01, ***P<0.001. P=0.001 for P4HB; P<0.001 for PDIA3 between oligodendroglioma (OD) and GBM; P=0.002 for P4HB; P=0.001 for PDIA3 between oligoastrocytoma (OA) and GBM; P=0.001 for P4HB; P<0.001 for PDIA3 between astrocytoma (A) and GBM.
Figure 5.
Figure 5.
Effects of PDIA3 on glioma cell proliferation, apoptosis and migration in vitro. (A) Relative PDIA3 expression in U87 and U251 cells transfected with siRNA against PDIA3 (si-PDIA3) and negative control (si-NC). (B) CCK-8 assay, (C) colony formation assay, (D) Hoechst staining and (E) Scratch assay were performed to test the biological functions of U87 and U251 cells. **P<0.01.
Figure 6.
Figure 6.
Kaplan-Meier survival curve analysis of glioma patients with chemotherapy (n=330) or radiotherapy (n=388) in TCGA based on the expression of P4HB (A) and PDIA3 (B). Cell growth inhibition test (C) and colony formation assay (D) were performed to determine the biological functions of U251 cells after knockdown of PDIA3 plus temozolomide (TMZ) treatment.
See this image and copyright information in PMC

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