Background
Gliomas are one of the most common malignant tumors in the central nervous system (CNS) and account for nearly 75% primary tumors in adults1. According to the histopathological features and prognostic factors, World Health Organization (WHO) classified gliomas into four grades (I-IV), from which the glioblastomas (GBMs) are categorized as the most malignant subtype (grade IV)2. The tradition multimodal therapeutic strategies against gliomas, which include advanced neurosurgery, radiation and chemotherapy, cannot dramatically improve the prognosis in glioma patients. Patients with GBM still have dismal prognosis, with median overall survival time less than 17 months3. The tolerance against multiple treatments and invariably relapse of gliomas are extensively studied as consequences of molecular or chromosomal subtypes, oncogenic activations and distinct metabolic immunosuppressive tumor microenvironment (TME)3-6. Pursuing better understanding of molecular landscape in gliomas, novel markers are successively detected with important clinical significance. Various discoveries, such as promoter mutations in TERT, mutations in IDH1/IDH2, co-deletion of chromosome arms 1p/19q and H2K27M-mutant are clearly associated with improved homogeneity in clinical outcomes and are referred as critical predictors in clinical practice3,7-9. Further strengthening the knowledge of such molecular alterations will definitely benefit our perception of gliomas from different perspectives. In this regard, investigate novel molecular biomarkers or driver genes will facilitate the establishment of comprehensive understanding about tumor promotion and the development of better therapeutic strategies to cure this disease.
The protein disulfide isomerases (PDIs) were originally discovered to enrich in endoplasmic reticulum (ER) and participate into the procedures of protein folding10. Encoded by P4HB gene, PDI is a 57-kDa redox-dependent protein with multi-domain structure11. Performing as critical ER enzymes, PDIs majorly involve in the oxidoreductase and chaperone activities which mediate the redox state and maintain the proper folding and function of proteins11,12. The biological functions of PDIs are identified as reductase, oxidase and chaperone in ER which have been associated with abundant physiopathologic mechanisms, such as infection, coagulation, cellular viability, neurodegeneration and immunization10,13-16. PDIA4, one of the largest PDI members, comprises 645 amino acids and three classical CGHC active motifs. Similar to other PDI members, PDIA4 initiates coagulation and enhances formation of thrombus via series cascades reaction17. Besides the classic biological functions of PDIA4, emerging evidence indicate the potential association between PDIA4 and the development of tumor17. The upregulated expression of PDIA4 was detected in a variety of tumor cell lines as well as human lung adenocarcinoma tissue, the expression of PDIA4 mediates the inhibition of mitochondrial apoptosis-induced tumor death18. Further study revealed that PDIA4 promotes tumor progression through the reduction of caspases 3/712. The ectopic expression and function of PDIA4 had also been reported in ovarian cancer. In ovarian carcinoma, PDIA4 was found to take part in the drug-resistance phenotype and can serve as a critical prognostic marker19,20. Moreover, in pancreatic carcinoma, hepatocellular carcinoma and esophageal squamous cell carcinoma, the increased expression of PDIA4 was respectively observed and associated with tumor development21-25. In our previous studies, we have already described PDIA4 as one of the prognostic markers in lower-grade gliomas and the potential association between PDIA4 and immunosuppressive TME26. From this perspective, we conduct further experiments to study the molecular mechanisms and behaviors of PDIA4 in gliomas.