Dataset Information

IGFBP2 from a novel copper metabolism-associated biomarker promoted glioma progression and response to immunotherapy.

ABSTRACT:

Introduction

Copper metabolism encompasses all cellular metabolic processes involving copper ions and plays a significant role in the pathogenesis of diseases, including cancer. Furthermore, copper is intricately involved in various processes related to nucleotide metabolism. However, a comprehensive analysis of copper metabolism in gliomas remains lacking despite its importance.

Methods

To address this gap, glioma patients were stratified based on the expression levels of copper metabolism-related genes. By utilizing machine learning techniques, a novel copper metabolism-associated biomarker was developed. The potential of this biomarker in prognosis, mutation analysis, and predicting immunotherapy response efficiency in gliomas was systematically investigated.

Results

Notably, IGFBP2, identified as a glioma tumor promoter, was found to promote disease progression and influence immunotherapy response. Additionally, glioma-derived IGFBP2 was observed to enhance microglial migration. High IGFBP2 expression in GBM cells facilitated macrophage interactions through the EGFR, CD63, ITGB1, and CD44 signaling pathways. Discussion: Overall, the copper metabolism-associated biomarker shows promising potential to enhance the clinical management of gliomas, offering valuable insights into disease prognosis and treatment strategies.

SUBMITTER: Luo Q

PROVIDER: S-EPMC10620745 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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IGFBP2 from a novel copper metabolism-associated biomarker promoted glioma progression and response to immunotherapy.

Luo Qisheng Q Zhuang Junhong J Zheng Dandan D Miao Changfeng C Luo Hongcheng H Peng Jun J Zheng Chuanhua C Qin Chengjian C Lan Chuanliu C Chen Meiqin M Xia Ying Y Huang Deyou D Chen Zigui Z

Frontiers in immunology 20231019

<h4>Introduction</h4>Copper metabolism encompasses all cellular metabolic processes involving copper ions and plays a significant role in the pathogenesis of diseases, including cancer. Furthermore, copper is intricately involved in various processes related to nucleotide metabolism. However, a comprehensive analysis of copper metabolism in gliomas remains lacking despite its importance.<h4>Methods</h4>To address this gap, glioma patients were stratified based on the expression levels of copper ...[more]

PMID: 37928523

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Project description:BackgroundGlioma, an aggressive brain tumor, poses a challenge in understanding the mechanisms of treatment resistance, despite promising results from immunotherapy.MethodsGenes associated with immunotherapy resistance were identified by analyzing The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and the Gene Expression Omnibus (GEO) database. In addition, gene set enrichment analysis (GSEA) was utilized to reveal relevant signaling pathways. Co-expression, differential expression and functional analyses were performed using TCGA-GBM/LGG, TIMER 2.0, MetScape, GTEx and LinkedOmics databases. Relationships with immune infiltration, ferroptosis and immune checkpoint genes were assessed. Gene mutations were explored by cBioPortal. Logistic regression, Lasso analysis, Receiver Operating Characteristic (ROC), Kaplan-Meier analysis, and Nomogram modeling assessed the correlation between MFAP4 and clinicopathological features of gliomas. By analyzing different datasets, we found that MFAP4 was aberrantly overexpressed in gliomas and correlated with poor clinicopathological features of gliomas. MFAP4 was an independent prognostic indicator and significantly correlated with glioma progression. We also performed functional and pathway enrichment analyses of MFAP4 in gliomas to explore its biological functions and potential molecular mechanisms in gliomas.ResultsMFAP4 was significantly elevated in glioma tissues compared to controls. MFAP4-related genes showed differential expression in pathways involving cytokines. Significant associations between MFAP4 levels, immune infiltration, ferroptosis, and immune checkpoint genes were found in glioma tissues. MFAP4 levels were correlated with glioma stage, histological type, and 1p/19q status, and independently predicted overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI). MFAP4 expression is effective in distinguishing tumor tissue from normal brain tissue. Furthermore, Spearman Correlation emphasizes the significant relationship between MFAP4 and ferroptosis-related genes.ConclusionOur study demonstrated that MFAP4 is aberrantly overexpressed in gliomas and correlates with adverse clinicopathological features. MFAP4 has relevance in regulating both tumor immunity and iron death, and cellular function assays have demonstrated that MFAP4 promotes the proliferation, migration, and invasion of glioma cells.

Project description:BackgroundDNA damage response (DDR) proficiency is the principal mechanism of temozolomide (TMZ) resistance in glioma. Accumulating evidence has also suggested the determining role of DDR in anticancer immunity. We propose that a comprehensive investigation of the DDR landscape can optimize glioma treatment.MethodsWe identified the pronounced enrichment of DDR in TMZ-resistant glioma cells by RNA sequencing. Nine differentially expressed genes between TMZ-sensitive/resistant glioma cells were selected to construct the DDR score through lasso regression analysis. Two glioma cohorts from TCGA and CGGA were interrogated to evaluate the predictive ability of DDR score. Multiple algorithms were applied to estimate the immunotherapeutic responses of two DDR phenotypes. Immunohistochemistry was used to determine the protein levels of PD-L1 and TGFβ in glioma specimens. The oncoPredict package was employed to predict the candidate chemotherapy agents.ResultsDDR score exhibited a robust prognostic capability in TCGA and CGGA cohorts and served as an independent predictive biomarker in glioma patients. Functional enrichment analyses revealed that high and low DDR score groups were characterized by distinct immune activity and metabolic processes. Elevated levels of infiltrating immune cells (including CD8+ T cells, CD4+ T cells, and dendritic cells) were observed in the high DDR score glioma. Further, high DDR scores correlated with increased mutation burden, up-regulated immune checkpoints, and tumor immunity activation, indicating a profound interplay between DDR score and glioma immunogenicity. In addition, PD-L1 and TGFβ were overexpressed in recurrent glioma specimens compared with primary ones. Finally, we estimated that PI3K inhibitors may serve as latent regimens for high DDR score patients.ConclusionOur study highlighted the promising prognostic role of DDR score in glioma. Individual assessment of DDR status for patients with glioma may provide new clues for developing immunotherapeutic strategies.

Project description:BackgroundGlioma is one of the most common malignancies in the central nervous system and has limited effective therapeutic options. Therefore, we sought to identify a suitable target for immunotherapy.Materials and methodsWe screened prognostic genes for glioma in the CGGA database and GSE43378 dataset using survival analysis, receiver operating characteristic (ROC) curves, independent prognostic analysis, and clinical correlation analysis. The results were intersected with immune genes from the ImmPort database through Venn diagrams to obtain likely target genes. The target genes were validated as prognostically relevant immune genes for glioma using survival, ROC curve, independent prognostic, and clinical correlation analyses in samples from the CGGA database and GSE43378 dataset, respectively. We also constructed a nomogram using statistically significant glioma prognostic factors in the CGGA samples and verified their sensitivity and specificity with ROC curves. The functions, pathways, and co-expression-related genes for the glioma target genes were assessed using PPI networks, enrichment analysis, and correlation analysis. The correlation between target gene expression and immune cell infiltration in glioma and the relationship with the survival of glioma patients were investigated using the TIMER database. Finally, target gene expression in normal brain, low-grade glioma, and high-grade glioma tissues was detected using immunohistochemical staining.ResultsWe identified TNFRSF12A as the target gene. Satisfactory results from survival, ROC curve, independent prognosis, and clinical correlation analyses in the CGGA and GSE43378 samples verified that TNFRSF12A was significantly associated with the prognosis of glioma patients. A nomogram was constructed using glioma prognostic correlates, including TNFRSF12A expression, primary-recurrent-secondary (PRS) type, grade, age, chemotherapy, IDH mutation, and 1p19q co-deletion in CGGA samples with an AUC value of 0.860, which illustrated the accuracy of the prognosis prediction. The results of the TIMER analysis validated the significant correlation of TNFRSF12A with immune cell infiltration and glioma survival. The immunohistochemical staining results verified the progressive up-regulation of TNFRSF12A expression in normal brain, low-grade glioma, and high-grade glioma tissues.ConclusionWe concluded that TNFRSF12A was a viable prognostic biomarker and a potential immunotherapeutic target for glioma.

Dataset Information

IGFBP2 from a novel copper metabolism-associated biomarker promoted glioma progression and response to immunotherapy.

Introduction

Methods

Results

Publications

IGFBP2 from a novel copper metabolism-associated biomarker promoted glioma progression and response to immunotherapy.

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