Introduction Increasing evidence has revealed the key activity of protein disulfide isomerase A4 (PDIA4) in the endoplasmic reticulum stress (ERS) response. However, the role of PDIA4 in regulating glioblastoma (GBM)-specific pro-angiogenesis is still unknown. Methods The expression and prognostic role of PDIA4 were analyzed using a bioinformatics approach and were validated in 32 clinical samples and follow-up data. 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. 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. Cell migration and tube formation assays determined the pro-angiogenesis activity of PDIA4 in vitro. An intracranial U87 xenograft GBM animal model was constructed to evaluate the pro-angiogenesis role of PDIA4 in vivo. Results Aberrant 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. 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). The XBP1/PDIA4/VEGFA axis partially supports the mechanism underlying GBM cell survival under ER stress. Further, GBM cells with higher expression of PDIA4 showed resistance to antiangiogenic therapy in vivo. Conclusions Our findings revealed the pro-angiogenesis role of PDIA4 in GBM progression and its potential impact on GBM survival under a harsh microenvironment. Targeting PDIA4 might help to improve the efficacy of antiangiogenic therapy in patients with GBM.

Objective Leukocyte‐associated immunoglobulin‐like receptor‐1 (LAIR‐1), is an immunosuppressive receptor, widely expressed by immune cells, but the part of LAIR‐1 in glioma progression remains unclear. The purpose of this study was to explore the relationship between LAIR‐1 expression and the development of lower‐grade glioma (LGG) using publicly available data sets. Methods We took advantage of The Cancer Genome Atlas (TCGA) to analyze the expression of LAIR‐1 in patients with LGG. Second, Kaplan‐Meier methods and univariate and multivariate Cox regression analyses were used to examine the clinical significance of LAIR‐1 expression in combination with CGGA databases, and then receiver operating characteristic curve analysis was used to verify the prognostic utility of LAIR‐1. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were used to explore the function of LAIR‐1. Analysis of the correlation with immune infiltration was conducted using the ESTIMATE algorithm and single sample gene set enrichment analysis. Results Our results showed that LAIR‐1 expression to be positively correlated with malignant clinicopathologic features of LGG. Univariate analysis and multivariate analysis revealed that overexpression of LAIR‐1 was correlated with a worse prognosis in patients. A nomogram model combining LAIR‐1 was more useful in guiding clinical diagnosis, and functional enrichment analysis showed that malignant development of glioma was closely affiliated with the tumor immune microenvironment. Conclusion These results indicate that LAIR 1 is a latent marker for determining the prognosis of LGG patients. LAIR 1 may also participate a critical part in TIME of LGG by regulating the infiltration of immune cells, suggesting that LAIR 1 might be used as a therapeutic target to regulate the antitumor immune response.