![]() For example, PDIA3 expression of GBM cells can enhance the pro-tumor ability of macrophage/microglia, and knock-out Pdia3 in mice CDD8 + T cells can promote the GBM-killing capacity of T cells in vivo PDIA4 and PDIA6 contributes to the cisplatin resistance of lung adenocarcinoma PDIA6 also regulates the EGFR-dependent migratory and invasive abilities of GBM cells. These enzymes have oxidoreductase and protein chaperone activities, and increasing evidence has indicated that PDI functions play a vital role in cancer proliferation, metastasis, drug resistance, and immune escape activities. Protein disulfide isomerases (PDI) are a series of multifunctional proteins that maintain intracellular homeostasis by regulating the formation of disulfide bonds and correct protein folding, and have been reported to be involved in carcinogenesis and progression. Therefore, the search for new targets and the availability of new treatment strategies for GBM is critical and urgently needed for both patients and clinicians. Although, despite the advances in biomedical technology in recent years, novel treatment approaches and the discouraging prognosis of patients with GBM have not been significantly improved. General treatment of GBM includes surgical resection combined with postoperative chemotherapy and/or radiation therapy, which have been the main therapy strategies for several decades. GBM is biologically and pathologically characterized by aggressive infiltrating growth, immunological suppression by the microenvironment, and extensive neovascularization, all of which contribute to the evasion of GBM cells from immune clearance, increased survival in a harsh microenvironment, and poor prognosis and a high recurrence rate. Glioblastoma (GBM) multiforme poses an insurmountable challenge due to its poor clinical outcome and median overall survival (OS) of approximately 7 months without treatment. Targeting PDIA4 might help to improve the efficacy of antiangiogenic therapy in patients with GBM. Our findings revealed the pro-angiogenesis role of PDIA4 in GBM progression and its potential impact on GBM survival under a harsh microenvironment. Further, GBM cells with higher expression of PDIA4 showed resistance to antiangiogenic therapy in vivo. The XBP1/PDIA4/VEGFA axis partially supports the mechanism underlying GBM cell survival under ER stress. Functionally, PDIA4 exhibits pro-angiogenesis activity both in vitro and in vivo, and can be upregulated by ERS through transcriptional regulation of X-box binding protein 1 (XBP1). ResultsĪberrant overexpression of PDIA4 was associated with a poor prognosis in patients with GBM, although PDIA4 could also functionally regulate intrinsic GBM secretion of vascular endothelial growth factor-A (VEGF-A) through its active domains of Cys-X-X-Cys (CXXC) oxidoreductase. An intracranial U87 xenograft GBM animal model was constructed to evaluate the pro-angiogenesis role of PDIA4 in vivo. Cell migration and tube formation assays determined the pro-angiogenesis activity of PDIA4 in vitro. Western blotting, real-time quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assays (ELISA) were used to measure the levels of the involved factors. ![]() RNA-sequencing was used to search for PDIA4-associated biological processes in GBM cells, and proteomic mass spectrum (MS) analysis was used to screen for potential PDIA4 substrates. The expression and prognostic role of PDIA4 were analyzed using a bioinformatics approach and were validated in 32 clinical samples and follow-up data. ![]() However, the role of PDIA4 in regulating glioblastoma (GBM)-specific pro-angiogenesis is still unknown. Increasing evidence has revealed the key activity of protein disulfide isomerase A4 (PDIA4) in the endoplasmic reticulum stress (ERS) response. ![]()
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