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.