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Background: Previous evidences has highlighted the pivotal role of NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated inflammasomes and pyroptosis activation in driving tumor malignancy and shaping the tumor microenvironment. Herein, we aimed to elucidate the impact of high-mobility group box 3 (HMGB3) released in glioma-derived exosomes on macrophage infiltration in gliomas, NLRP3 inflammasome activation and polarization., Methods: Transcripts and protein levels of HMGB3, and cytokines associated with macrophage phenotypes and pyroptosis were assessed in glioma tissues and cell lines (U251, LN229, T98G, A172) using qRT-PCR and/or Western blot analysis. Exosomes secreted from LN229 and NHA cells were isolated via differential ultracentrifugation and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and analysis of exosome-related markers. PKH67 staining was employed to examine exosomes uptake by THP-1 differentiated macrophages. Flow cytometry was utilized to assess macrophage pyroptotic rates and polarization-related markers., Results: HMGB3 expression was elevated in glioma tissues, serum samples and tumor cell lines. Kaplan-Meier curves revealed a positive correlation between higher HMGB3 expression and poor overall survival and recurrence-free survival. Moreover, glioma tissues with increased HMGB3 expression exhibited significant upregulation of M2 macrophages markers (CD68, CD206, Arg1) and NLRP3 inflammasome components (NLRP3, IL-1β, ASC), suggesting that HMGB3 was closely associated with macrophage infiltration and NLRP3 inflammasome activation. Notably, HMGB3 was found to be enriched in glioma cell- secreted exosomes and could be internalized by macrophages. Knockdown of HMGB3 in glioma cell exosomes could restrain M2 macrophage polarization, NLRP3 inflammasome activation and pyroptosis., Conclusion: These findings suggested that glioma cells secreted exosomal HMGB3 could facilitate macrophage M2 polarization, pyroptosis and inflammatory infiltration, indicating HMGB3 might be a poor prognosis factor for glioma., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. The unregulated expression of Claudin-4 (CLDN4) plays an important role in tumor progression. However, the biological role of CLDN4 in GBM is still unknown. This study aimed to determine whether CLDN4 mediates glioma malignant progression, if so, it would further explore the molecular mechanisms of carcinogenesis. Our results revealed that CLDN4 was significantly upregulated in glioma specimens and cells. The inhibition of CLND4 expression could inhibit mesenchymal transformation, cell invasion, cell migration and tumor growth in vitro and in vivo. Moreover, combined with in vitro analysis, we found that CLDN4 can modulate tumor necrosis factor-α (TNF-α) signal pathway. Meanwhile, we also validated that the transforming growth factor-β (TGF-β) signal pathway can upregulate the expression of CLDN4, and promote the invasion ability of GBM cells. Conversely, TGF-β signal pathway inhibitor ITD-1 can downregulate the expression of CLDN4, and inhibit the invasion ability of GBM cells. Furthermore, we found that TGF-β can promote the nuclear translocation of CLDN4. In summary, our findings indicated that the TGF-β/CLDN4/TNF-α/NF-κB signal axis plays a key role in the biological progression of glioma. Disrupting the function of this signal axis may represent a new treatment strategy for patients with GBM., (© 2022. The Author(s).)

Simple Summary: Glioma is a malignant primary brain tumor accounting for 75% of the total cases. Notably, several immunotherapeutic and chemotherapeutic agents in glioma have been demonstrated to induce immunogenic cell death (ICD). However, the studies on glioma have targeted individual ICD-related genes, and comprehensive analyses of all the ICD-related genes are still lacking. The aim of this study was to identify a novel molecular signature based on ICD-related genes in glioma, which might be beneficial for the diagnosis and treatment of glioma. We eventually identified a 14 ICD-related gene signature, which could effectively predict prognosis and immunotherapy response in glioma. These findings might be significantly helpful in selecting the best therapeutic strategy for glioma. Immunogenic cell death (ICD) is a type of regulated cell death (RCD) and is correlated with the progression, prognosis, and therapy of tumors, including glioma. Numerous studies have shown that the immunotherapeutic and chemotherapeutic agents of glioma might induce ICD. However, studies on the comprehensive analysis of the role of ICD-related genes and their correlations with overall survival (OS) in glioma are lacking. The genetic, transcriptional, and clinical data of 1896 glioma samples were acquired from five distinct databases and analyzed in terms of genes and transcription levels. The method of consensus unsupervised clustering divided the patients into two disparate molecular clusters: A and B. All of the patients were randomly divided into training and testing groups. Employing the training group data, 14 ICD-related genes were filtered out to develop a risk-score model. The correlations between our risk groups and prognosis, cells in the tumor microenvironment (TME) and immune cells infiltration, chemosensitivity and cancer stem cell (CSC) index were assessed. A highly precise nomogram model was constructed to enhance and optimize the clinical application of the risk score. The results demonstrated that the risk score could independently predict the OS rate and the immunotherapeutic response of glioma patients. This study analyzed the ICD-related genes in glioma and evaluated their role in the OS, clinicopathological characteristics, TME and immune cell infiltration of glioma. Our results may help in assessing the OS of glioma and developing better immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

The Fc Fragment of IgG Binding Protein (FCGBP) has been proven to participate in intestinal tumor immunity. However, the biological role of FCGBP has remained unclear in glioma. The differential expression of FCGBP was explored by Oncomine and GEPIA databases. The effect of FCGBP on prognosis was analyzed via Kaplan–Meier plotter and GEPIA. The Tumor Immune Estimation Resource (TIMER) tool was used to determine the correlations of FCGBP expression with tumor immune infiltration. Firstly, FCGBP was highly expressed in glioma and correlated with a worse prognosis. Gene Ontology (GO) and KEGG pathway enrichment analyses revealed that the differentially expressed genes (DEGs) and co-expression genes of FCGBP were mainly involved in the immune response. Furthermore, FCGBP expression was positively associated with multiple immune cells infiltrates as well as the expression levels of multiple immune markers in glioma. FCGBP co-expression networks mostly participated in the regulation of immune response. Finally, immunohistochemistry (IHC) assays were conducted to explore the expression of FCGBP, PD-L1, CCL2 and CD8 in glioma and correlations between them. We found that PDL1 and FCGBP were synchronously upregulated in glioma tissues. These findings revealed a new mechanism by which FCGBP participates in the immune tolerance of glioma, and implied the potential of FCGBP as a therapeutic target or predictive marker for patients. [ABSTRACT FROM AUTHOR]