Integrated analysis of programmed cell death ligand 1 expression reveals increased levels in high-grade glioma

Hölzl, Dorothee; Hutarew, Georg; Zellinger, Barbara; Schlicker, H.; Schwartz, Christoph; Winkler, Peter; Sotlar, Karl; Kraus, Theo

doi:10.1007/s00432-021-03656-w

Cited by 14 publications

(12 citation statements)

References 36 publications

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“…Its expression in glioblastoma tumor tissue or possible mechanism remains unclear. In addition, PET using the TSPO radiation ligand is not a standard imaging modality for patients with brain tumors (Zhang et al, 2020;Yang T. et al, 2021;Holzl et al, 2021). The relationship between CD31 + and TSPO + endothelial cells is found in blood vessels of different sizes, including capillaries (Huang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Role of the TSPO–NOX4 axis in angiogenesis in glioblastoma

Jiang

Li²,

Cai³

et al. 2022

Front. Pharmacol.

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Objective: Angiogenesis is a pathological feature of glioblastoma. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is a vital source of reactive oxygen species (ROS) related to angiogenesis. However, signaling pathways correlated with the isoform oxidase are unknown. The aim of this study was to elucidate the detailed mechanism of the role of NOX4 in angiogenesis in glioblastoma.Methods: Public datasets were searched for studies on immunohistochemistry and western blotting to evaluate NOX4 expression in glioma. The location of NOX4 expression was detected by immunofluorescence. We conducted conditional deletion of the translocator protein (TSPO) targeting the protein with the synthetic ligand XBD173 in the glioblastoma mouse model. NOX4 downregulation was conducted with the NOX4 inhibitor GLX351322, and ROS production and angiogenesis were detected in glioma tissues.Results: Clinical samples and public datasets showed that NOX4 was upregulated and associated with the prognosis. NOX4 is mainly expressed in endothelial cells of glioblastoma. Both TSPO and NOX4 promoted angiogenesis in an ROS-dependent manner, suggesting that TSPO triggered ROS production in glioblastoma via NOX4.Conclusion: These results showed that TSPO is an upstream target of NOX4-derived mitochondrial ROS, which is indispensable for NOX4-derived mitochondrial ROS-induced angiogenesis in glioblastoma. TSPO–NOX4 signaling could serve as a molecular target for therapeutic strategies for glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Role of the TSPO–NOX4 axis in angiogenesis in glioblastoma

Jiang

Li²,

Cai³

et al. 2022

Front. Pharmacol.

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“…ICPs may inhibit the over-activation of the immune system and prevent the occurrence of allergic reactions and autoimmune diseases ( 42 ). In gliomas, common ICPs include PD-1 ( 43 ) and PD-L1 ( 44 ). Immune checkpoint blockade (ICB) therapy may block the function of checkpoints and reactivate the over-suppressed immune system ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of γ‐aminobutyric acidergic synapse-associated signature for lower-grade gliomas

Jiang

Sun

et al. 2022

Front. Immunol.

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BackgroundSynapse-associated proteins (SAPs) play important roles in central nervous system (CNS) tumors. Recent studies have reported that γ-aminobutyric acidergic (GABAergic) synapses also play critical roles in the development of gliomas. However, biomarkers of GABAergic synapses in low-grade gliomas (LGGs) have not yet been reported.MethodsmRNA data from normal brain tissue and gliomas were obtained from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, respectively. A validation dataset was also obtained from the Chinese Glioma Genome Atlas (CGGA) database. The expression patterns of GABAergic synapse-related genes (GSRGs) were evaluated with difference analysis in LGGs. Then, a GABAergic synapse-related risk signature (GSRS) was constructed with least absolute shrinkage and selection operator (LASSO) Cox regression analysis. According to the expression value and coefficients of identified GSRGs, the risk scores of all LGG samples were calculated. Univariate and multivariate Cox regression analyses were conducted to evaluate related risk scores for prognostic ability. Correlations between characteristics of the tumor microenvironment (TME) and risk scores were explored with single-sample gene set enrichment analysis (ssGSEA) and immunity profiles in LGGs. The GSRS-related pathways were investigated by gene set variation analysis (GSVA). Real-time PCR and the Human Protein Atlas (HPA) database were applied to explore related expression of hub genes selected in the GSRS.ResultsCompared with normal brain samples, 25 genes of 31 GSRGs were differentially expressed in LGG samples. A constructed five-gene GSRS was related to clinicopathological features and prognosis of LGGs by the LASSO algorithm. It was shown that the risk score level was positively related to the infiltrating level of native CD4 T cells and activated dendritic cells. GSVA identified several cancer-related pathways associated with the GSRS, such as P53 pathways and the JAK-STAT signaling pathway. Additionally, CA2, PTEN, OXTR, and SLC6A1 (hub genes identified in the GSRS) were regarded as the potential predictors in LGGs.ConclusionA new five-gene GSRS was identified and verified by bioinformatics methods. The GSRS provides a new perspective in LGG that may contribute to more accurate prediction of prognosis of LGGs.

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“…These markers were used only for routine diagnostics; there was no significant difference of GFAP and Ki67 expression in the two PD-L1 groups ( Supplementary Table S1 and Supplementary Figure S1 ). PD-L1 expression was assessed by applying the PD-L1 22C3 antibody (M3653 kit antibody, Dako/Agilent, Santa Clara, CA, USA), and [ 19 ]; PD-L1 levels were quantified using the tumor proportion score (TPS) [ 23 , 24 , 25 ]. To determine the TPS, we counted the tumor cells with membranous positive staining and determined the fraction of PD-L1-positive tumor cells.…”

Section: Methodsmentioning

confidence: 99%

“…Thereby, an overexpression of PD-L1 as a druggable target [ 10 , 11 , 12 , 13 , 14 , 15 ] can be found in many tumors, e.g., lung, breast, and gastrointestinal cancer, and is associated with good response-applying PD-L1 inhibitors [ 16 , 17 , 18 ]. Indeed, PD-L1 overexpression has recently been detected in a subset of gliomas [ 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Methylome Profiling of PD-L1-Expressing Glioblastomas Shows Enrichment of Post-Transcriptional and RNA-Associated Gene Regulation

Hutarew

Hölzl

Schiefer

et al. 2022

Cancers

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Glioblastomas are the most frequent primary brain tumors in adults. They show highly malignant behavior and devastating outcomes. Since there are still no targeted therapies available, median survival remains in the range of 12 to 15 months for glioblastoma patients. Programmed Cell Death Ligand 1 (PD-L1) is a promising novel candidate in precision medicine. Here, we performed integrated epigenome-wide methylation profiling of 866,895 methylation-specific sites in 20 glioblastoma samples comparing PD-L1 high- (i.e., TPS (tumor proportion score) > 30%) and PD-L1 low-expressing glioblastomas (i.e., TPS < 10%). We found 12,597 significantly differentially methylated CpGs (DMCG) (Δβ ≥ 0.1 and p-value < 0.05) in PD-L1 high- compared with PD-L1 low-expressing glioblastomas. These DMCGs were annotated to 2546 tiling regions, 139 promoters, 107 genes, and 107 CpG islands. PD-L1 high-expressing glioblastomas showed hypomethylation in 68% of all DMCGs. Interestingly, the list of the top 100 significantly differentially methylated genes showed the enrichment of regulatory RNAs with 19 DMCGs in miRNA, snoRNAs, lincRNAs, and asRNAs. Gene Ontology analysis showed the enrichment of post-transcriptional and RNA-associated pathways in the hypermethylated gene regions. In summary, dissecting the methylomes depending on PD-L1 status revealed significant alterations in RNA regulation and novel molecular targets in glioblastomas.

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Integrated analysis of programmed cell death ligand 1 expression reveals increased levels in high-grade glioma

Cited by 14 publications

References 36 publications

Role of the TSPO–NOX4 axis in angiogenesis in glioblastoma

Role of the TSPO–NOX4 axis in angiogenesis in glioblastoma

Prognostic value of γ‐aminobutyric acidergic synapse-associated signature for lower-grade gliomas

Methylome Profiling of PD-L1-Expressing Glioblastomas Shows Enrichment of Post-Transcriptional and RNA-Associated Gene Regulation

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