Discussion
Despite the current multi-therapeutic strategies against glioma, including modern neurosurgery, radiotherapy, chemotherapy and immunotherapy, the prognosis of glioma patients remains poor due to the aggressive features of this type of cancer. Novel efficient management for glioma requires comprehensive understanding of the biological nature of this disease. The illustration of potential critical factors which overexpress and play essential role in glioma progression is of great importance to increase our knowledge of this malignant disease. Our present study first identified PDIA4 is a novel molecular marker which shows close relationship with the clinicopathological characters and immunological surveillance of glioma, and provides alternative strategies for the subsequent treatment of this disease.
PDIA4 was originally described to present in various biological processes, including coagulation33, thrombosis formation34,35and injury reaction36. Recently, mounting evidence reported the aberrant expression and the potential mechanisms of PDIA4 participates in the development of multiple types of cancer12,17,18,21. Moreover, our recent study documented that PDIA4 involved in the prognostic model in LGG, subsequently participating in the immunosuppressive TME26. Based on these findings, the present study identified PDIA4 was not only overexpressed in glioma tissues, but also significantly consistent with WHO grade. Mechanistically, PDIA4 was significantly associated with the IDH status and different subtypes of glioma. Also, our study revealed increased mRNA expression of PDIA4 in glioma cell lines. Furthermore, we examined the clinical importance of PDIA4 and found PDIA4 was an independent prognostic marker whose expression was negatively correlated with outcomes of patients with glioma. To elucidate the critical functions of PDIA4 in glioma, we conducted GO function and KEGG pathway analysis in both TCGA and CGGA datasets. As a result, the PDIA4-related biological functions were mainly enriched in transferase activities, endoplasmic reticulum responses and immunities.
The orchestrated immunological interactions within glioma TME have received increased focus and harnessing the immune system is becoming a hotspot in the field of oncology. Various components of glioma TME, such as immune cells, cytokines and markers are coordinately interact with each other to establish the immunosuppressive phenotype and promote the development of glioma5. From this perspective, advanced clinical practices by targeting specific immunotherapies have already showed profound outcomes compared to conventional therapy against glioma. As PDIA4 was previously revealed to participate in the immunological TME in LGG, we further detected its correlation with multiple immune factors. Consistent with our further study, we found PDIA4 was tightly related to both the immune and stromal scores in LGG. The relationship between PDIA4 and immune scores was relatively lower in GBM, which suggested the potential heterogeneities between different grades of glioma. After checking the association between PDIA4 and 64 non-cancerous cells, we found significant linkage between 46 types of cell and PDIA4. Furthermore, we studied the connections between PDIA4 and classic genes and markers of immune cells. Interestingly, the dada showed close relationship with several infiltrating immune cells, such as monocytes, tumor-associated macrophage and neutrophils, which are widely considered as immunosuppressive components in glioma TME. Association had also been detected among markers of dendritic cells and PDIA4, which suggested us the potential functions of PDIA4 in the process of antigen presentation and immune surveillance. Consistently, our PPI analysis of PDIA4 indicated that the major proteins related to PDIA4 are members of heat shock proteins or endoplasmic reticulum proteins which had also been reported as tumor promoting in various cancers21,37-40.