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.