Prognosis and therapeutic significance of IGF-1R-related signaling pathway gene signature in glioma.

Background: Glioma is the most common cancer of the central nervous system with poor therapeutic response and clinical prognosis. Insulin-like growth factor 1 receptor (IGF-1R) signaling is implicated in tumor development and progression and induces apoptosis of cancer cells following functional inhibition. However, the relationship between the IGF-1R-related signaling pathway genes and glioma prognosis or immunotherapy/chemotherapy is poorly understood. Methods: LASSO-Cox regression was employed to develop a 16-gene risk signature in the TCGA-GBMLGG cohort, and all patients with glioma were divided into low-risk and high-risk subgroups. The relationships between the risk signature and the tumor immune microenvironment (TIME), immunotherapy response, and chemotherapy response were then analyzed. Immunohistochemistry was used to evaluate the HSP90B1 level in clinical glioma tissue. Results: The gene risk signature yielded superior predictive efficacy in prognosis (5-year area under the curve: 0.875) and can therefore serve as an independent prognostic indicator in patients with glioma. The high-risk subgroup exhibited abundant immune infltration and elevated immune checkpoint gene expression within the TIME. Subsequent analysis revealed that patients in the high-risk subgroup benefited more from chemotherapy. Immunohistochemical analysis confirmed that HSP90B1 was overexpressed in glioma, with significantly higher levels observed in glioblastoma than in astrocytoma or oligodendrocytoma. Conclusion: The newly identified 16-gene risk signature demonstrates a robust predictive capacity for glioma prognosis and plays a pivotal role in the TIME, thereby offering valuable insights for the exploration of novel biomarkers and targeted therapeutics.

Multi-cohort comprehensive analysis unveiling the clinical value and therapeutic effect of GNAL in glioma.

Clinical data indicates that glioma patients have poor treatment outcomes and clinical prognosis. The role of olfactory signaling pathway-related genes (OSPRGs) in glioma has not been fully elucidated. In this study, we aimed to investigate the role and relationship between OSPRGs and glioma. Univariate and multivariate Cox regression analyses were performed to assess the relationship between OSPRGs and the overall survival of glioma based on public cohorts, and the target gene (G Protein Subunit Alpha L, GNAL) was screened. The association of GNAL expression with clinicopathological characteristics, gene mutation landscape, tumor immune microenvironment (TIME), deoxyribonucleic acid (DNA) methylation, and naris-occlusion controlled genes (NOCGs) was performed. Immunohistochemistry was used to evaluate GNAL level in glioma. Further analysis was conducted to evaluate the drug sensitivity, immunotherapy response, and functional enrichment of GNAL. GNAL was an independent prognostic factor, and patients with low GNAL expression have a poor prognosis. Expression of GNAL was closely associated with clinicopathological characteristics, DNA methylation, and several immune-related pathways. Immune infiltration analysis indicated that GNAL levels were negatively correlated with immune scores. GNAL low-expression group showed efficacy with anti-PD-1 therapy. Ten compounds with significantly different half-maximal inhibitory concentration (IC50) values between the GNAL high and low-expression groups were identified. Furthermore, its expression was associated with several immune cells, immune-related genes, and NOCGs. The expression of GNAL is closely associated with clinicopathological characteristics, TIME, and the response to therapeutic interventions, highlighting its potential as a prognostic biomarker for glioma.

H2S inhibits LiCl/pilocarpine-induced seizures and promotes neuroprotection by regulating TRPV2 expression via the AC3/cAMP/PKA pathway.

It is widely acknowledged that epilepsy is a neurological disorder characterized by recurrent and atypical neuronal discharges, resulting in transient dysfunction within the brain. The protective role of hydrogen sulfide (H2S) in epilepsy has been elucidated by recent studies, but the underlying mechanisms remain poorly understood. To investigate this, the concentration of H2S was measured by spectrophotometry and a fluorescent probe in LiCl/Pilocarpine (LiCl/Pilo)-induced seizures in rats. The localization of proteins was examined using immunofluorescence. Electroencephalogram and behavioral tests were employed to evaluate the occurrence of seizures. Neuropathological changes in the hippocampus were examined by hematoxylin-eosin staining, Nissl staining, and transmission electron microscopy. Through proteomics and bioinformatics analysis, we identified the differential proteins in the hippocampus of rats following H2S intervention. Protein changes were detected through western blotting. The results showed that H2S treatment significantly alleviated seizures and minimized post-seizures neurological damage in rats. Proteomics analysis revealed adenylate cyclase 3 (AC3) as a protein potentially targeted by H2S. Moreover, the AC3 activator forskolin reversed the downregulation effect of H2S on the AC3/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/transient receptor potential vanilloid 2 (TRPV2) signaling pathway. In conclusion, H2S targets and downregulates the expression of AC3, thereby modulating the AC3/cAMP/PKA signaling pathway to regulate the expression of TRPV2 in LiCl/Pilo-induced seizures, ultimately leading to seizure inhibition and neuroprotection.

Independent prognostic biomarker FERMT3 associated with immune infiltration and immunotherapy response in glioma.

BACKGROUND: Adult glioma progresses rapidly and has a poor clinical outcome. The focal adhesion protein Kindlin-3 (encoded by the FERMT3 gene) participates in tumor development, drug resistance, and progression. However, the relationship between Kindlin-3 and glioma prognosis or immune microenvironment is poorly understood. METHODS: We comprehensively analyzed the expression, prognostic value, mutation landscape, functional enrichment, immune infiltration, and therapeutic role of FERMT3 in glioma using multiple datasets and validated Kindlin-3 expression in clinical tissue specimens by immunohistochemistry and multiple immunofluorescence staining. RESULTS: FERMT3 is an independent predictor of glioma prognosis and is highly expressed in glioblastoma tissues. Functional enrichment analyses indicated that FERMT3 participates in multiple immune-related pathways such as immune response and cytokine production. Furthermore, FERMT3 expression was positively correlated with the infiltration of several immune cells, immune scores, and the expression of genes related to immune checkpoints. Further analyses revealed that overexpression of FERMT3 was linked to a better response to anti-PD1 therapy. Data from single-cell RNA-seq reveal that FERMT3 was largely expressed in microglial cells and tissue-resident macrophages. Multiple immunofluorescence staining confirmed the overexpression of Kindlin-3 in the glioma-associated microglia/macrophages (GAMs). CONCLUSION: The findings of this study provide a new perspective on the role of Kindlin-3 in glioma and may have a significant impact on the discovery of novel biomarkers and targeting of GAMs in the future.

Ferroptosis: A potential opportunity for intervention of pre-metastatic niche.

It is widely thought that the tumor microenvironment (TME) provides the "soil" for malignant tumors to survive. Prior to metastasis, the interaction at the host site between factors secreted by primary tumors, bone-marrow-derived cells, with stromal components initiates and establishes a pre-metastatic niche (PMN) characterized by immunosuppression, inflammation, angiogenesis and vascular permeability, as well as lymphangiogenesis, reprogramming and organotropism. Ferroptosis is a non-apoptotic cell death characterized by iron-dependent lipid peroxidation and metabolic constraints. Ferroptotic cancer cells release various signal molecules into the TME to either suppress or promote tumor progression. This review highlights the important role played by ferroptosis in PMN, focusing on the relationship between ferroptosis and PMN characteristics, and discusses future research directions.

Pyroptosis: a novel signature to predict prognosis and immunotherapy response in gliomas.

Gliomas are the most common primary brain tumors and are highly malignant with a poor prognosis. Pyroptosis, an inflammatory form of programmed cell death, promotes the inflammatory cell death of cancer. Studies have demonstrated that pyroptosis can promote the inflammatory cell death (ICD) of cancer, thus affecting the prognosis of cancer patients. Therefore, genes that control pyroptosis could be a promising candidate bio-indicator in tumor therapy. The function of pyroptosis-related genes (PRGs) in gliomas was investigated based on the Chinese Glioma Genome Atlas (CGGA), the Cancer Genome Atlas (TCGA) and the Repository of Molecular Brain Neoplasia Data (Rembrandt) databases. In this study, using the non-negative matrix factorization (NMF) clustering method, 26 PRGs from the RNA sequencing data were divided into two subgroups. The LASSO and Cox regression was used to develop a 4-gene (BAX, Caspase-4, Caspase-8, PLCG1) risk signature, and all glioma patients in the CGGA, TCGA and Rembrandt cohorts were divided into low- and high-risk groups. The results demonstrate that the gene risk signature related to clinical features can be used as an independent prognostic indicator in glioma patients. Moreover, the high-risk subtype had rich immune infiltration and high expression of immune checkpoint genes in the tumor immune microenvironment (TIME). The analysis of the Submap algorithm shows that patients in the high-risk group could benefit more from anti-PD1 treatment. The risk characteristics associated with pyroptosis proposed in this study play an essential role in TIME and can potentially predict the prognosis and immunotherapeutic response of glioma patients.

Emerging role of ferroptosis in glioblastoma: Therapeutic opportunities and challenges.

Glioblastoma (GBM) is the most common malignant craniocerebral tumor. The treatment of this cancer is difficult due to its high heterogeneity and immunosuppressive microenvironment. Ferroptosis is a newly found non-apoptotic regulatory cell death process that plays a vital role in a variety of brain diseases, including cerebral hemorrhage, neurodegenerative diseases, and primary or metastatic brain tumors. Recent studies have shown that targeting ferroptosis can be an effective strategy to overcome resistance to tumor therapy and immune escape mechanisms. This suggests that combining ferroptosis-based therapies with other treatments may be an effective strategy to improve the treatment of GBM. Here, we critically reviewed existing studies on the effect of ferroptosis on GBM therapies such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy. In particular, this review discussed the potential of ferroptosis inducers to reverse drug resistance and enhance the sensitivity of conventional cancer therapy in combination with ferroptosis. Finally, we highlighted the therapeutic opportunities and challenges facing the clinical application of ferroptosis-based therapies in GBM. The data generated here provide new insights and directions for future research on the significance of ferroptosis-based therapies in GBM.

Prognosis and Immunotherapy Significances of a Cancer-Associated Fibroblasts-Related Gene Signature in Gliomas.

As a cold tumor, malignant glioma has strong immunosuppression and immune escape characteristics. The tumor microenvironment (TME) provides the "soil" for the survival of malignant tumors, and cancer-associated fibroblasts (CAFs) are the architects of matrix remodeling in TME. Therefore, CAFs have potent regulatory effects on the recruitment and functional differentiation of immune cells, whereby they synthesize and secrete numerous collagens, cytokines, chemokines, and other soluble factors whose interaction with tumor cells creates an immunosuppressive TME. This consequently facilitates the immune escape of tumor cells. Targeting CAFs would improve the TME and enhance the efficacy of immunotherapy. Thus, regulation of CAFs and CAFs-related genes holds promise as effective immunotherapies for gliomas. Here, by analyzing the Chinese Glioma Genome Atlas and the Cancer Genome Atlas database, the proportion of CAFs in the tumor was revealed to be associated with clinical and immune characteristics of gliomas. Moreover, a risk model based on the expression of CAFs-related six-gene for the assessment of glioma patients was constructed using the least absolute shrinkage and selection operator and the results showed that a high-risk group had a higher expression of the CAFs-related six-genes and lower overall survival rates compared with those in the low-risk group. Additionally, patients in the high-risk group exhibited older age, high tumor grade, isocitrate dehydrogenase wildtype, 1p/19q non-codeletion, O-6-methylguanine-DNA methyltransferase promoter unmethylation and poor prognosis. The high-risk subtype had a high proportion CAFs in the TME of glioma, and a high expression of immune checkpoint genes. Analysis of the Submap algorithm indicated that the high-risk patients could show potent response to anti-PD-1 therapy. The established risk prediction model based on the expression of six CAFs-related genes has application prospects as an independent prognostic indicator and a predictor of the response of patients to immunotherapy.

EGFR/EGFRvIII partly regulates the tumourigenesis of glioblastoma through the SOX9-GLUT3 axis.

EGFR/EGFR variant III (EGFRvIII) glioblastoma is seriously malignant, and the underlying mechanism remains unclear. In this study, EGFR and GLUT3 were found to be co-expressed in our collected tissues and associated with worse overall survival in glioblastoma via bioinformatics analysis. Functionally, in vitro and in vivo tests revealed that silencing GLUT3 substantially inhibited the viability of U87-EGFRvIII and LN229-EGFRvIII cells. Compared with wild-type U87 or LN229 cells, the expression level of SOX9 in U87-EGFRvIII or LN229-EGFRvIII cells (U87 and LN229 over-expressing EGFRvIII) was substantially increased. Chromatin immunoprecipitation and Dual-luciferase reporter assays revealed that SOX9 bound to the promoter of GLUT3 and promoted the expression of GLUT3. Collectively, our findings indicated that the EGFR/EGFRvIII-SOX9-GLUT3 axis mediated the tumourigenesis of glioblastoma and might be a potential target for glioblastoma therapy.

Clinical and Biological Significances of a Ferroptosis-Related Gene Signature in Glioma.

Ferroptosis is a form of cell death characterized by non-apoptosis induced by small molecules in tumors. Studies have demonstrated that ferroptosis regulates the biological behaviors of tumors. Therefore, genes that control ferroptosis can be a promising candidate bioindicator in tumor therapy. Herein, functions of ferroptosis-related genes in glioma were investigated. We systematically assessed the relationship between ferroptosis-related genes expression profiles and prognosis in glioma patients based on The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) RNA sequencing datasets. Using the non-negative matrix factorization (NMF) clustering method, 84 ferroptosis-related genes in the RNA sequencing data were distinctly classified into two subgroups (named cluster 1 and cluster 2) in glioma. The least absolute shrinkage and selection operator (LASSO) was used to develop a 25 gene risk signature. The relationship between the gene risk signature and clinical features in glioma was characterized. Results show that the gene risk signature associated with clinical features can be as an independent prognostic indicator in glioma patients. Collectively, the ferroptosis-related risk signature presented in this study can potentially predict the outcome of glioma patients.