Glioma Development Research Articles

TMOD-12. DEFINING THE ROLE OF THE DAAM2 R414W GERMLINE VARIANT IN FAMILIAL GLIOMA

Abstract Malignant glioma is the most common primary brain tumor in adults, leading to high morbidity and mortality due to its aggressive nature and limited efficacious treatment options. To improve this prognosis, research has focused on genetic factors that may contribute to glioma. While most glioma cases arise from sporadic somatic mutations, approximately 5-10% are classified as familial glioma, stemming from inherited genetic variations. Although several studies have explored mechanisms behind somatic mutations in glioma, less is known about hereditary variants that promote glioma susceptibility. We recently discovered five germline mutations in Daam2 (Dishevelled associated activator of morphogenesis 2) from familial glioma patients. To examine the role of these mutations in familial glioma, we overexpressed these mutations in patient-derived glioma stem-like cells, which were subsequently orthotopically xenografted into immunodeficient mice. We identified that one of these mutations, Daam2-R414W, promotes tumor cell proliferation both in vitro and in vivo. To further understand the role of the Daam2-R414W mutation in familial glioma, we generated a knock-in immunocompetent mouse model with the Daam2-R414W mutation. In these mutant mice, we found an increased number of proliferating glial progenitor cells in the subventricular zone compared to Daam2 wildtype mice, suggesting the potential of the Daam2-R414W mutation to influence glial progenitor expansion to stimulate glioma initiation. Furthermore, to establish a potential mechanism, we performed proteomic profiling of Daam2 wildtype and Daam2-R414W overexpression tumors and found enrichment of Git1, a GTPase-activating protein involved in cytoskeletal remodeling, suggesting that the Daam2-R414W variant may interact with Git1 to promote tumor invasion. Our findings thus far identify a hereditary genetic variant with the potential to increase the risk of glioma, shedding light on the repercussions of a human developmental gene variant and its potential to disrupt normal cellular machinery to promote malignancy and glioma development.

EPID-19. INTERACTION BETWEEN GERMLINE AND SOMATIC GENETICS TO ELUCIDATE RISK OF ADULT DIFFUSE GLIOMA

Abstract Acquired tumor alterations are part of the WHO diagnosis of glioma. However, germline predisposition to these alterations is unknown. GWAS in European and Asian populations identified germline variants in 30 regions, many in or near genes that also acquire alterations, suggesting that interactions between inherited and acquired genetics are involved in glioma development. To evaluate such interactions, we used 3686 glioma cases and 1889 controls. A case-control design and multinomial logistic regression were used to identify germline variants associated with development of TERT-promoter mutant gliomas, generating two interesting observations. First, TERT germline variants were associated with predisposition to IDHwt glioma that have a TERT promoter mutation, but not with IDH-mutant codeleted gliomas that have a TERT promoter mutation. Second, two novel regions were observed in this more homogeneous subgroup of TERT mutated tumors: variants in TXNDC11 (OR=2.66, p=5.7x10-8) and RUVBL2 (OR=3.1, p=5.8x10-8). High tumor expression of TXNDC11 is associated with poor prognosis in glioma and RUVBL2 interacts with TERT to affect telomerase activity. Similar analyses are being performed on additional clinically relevant acquired alterations. In parallel, case-case GWAS analyses were performed to evaluate germline variants associated with other tumor alterations. Comparing IDH-mutant versus IDHwt stratified by rs55705857 genotype, the most significant variants were PHLDB1 (p=1.2x10-13) and D2HGDH (p=2.1x10-10), highlighting the importance of these two variants independent of CCDC26 for the development of IDH-mutant glioma. As a parallel approach, we utilized recursive partitioning and regression trees (rpart) to classify IDH mutation status using the 30 known variants. The top four branches of the regression tree included CCDC26, D2HGDH, PHLDB1, and MAML2, as well as two Asian variants (RAB27A, CYP4F12). This highlights the importance of utilizing variants discovered in non-European populations in analyses. Overall, understanding these interactions are necessary to develop therapeutics, stratify clinical trials, and to develop relevant tumor models.

BIOM-38. OPPOSING EFFECTS OF LINKED CX3CR1 GERMLINE VARIANTS ON INCIDENCE, SURVIVAL, AND IMMUNE ACTIVATION IN GLIOMA

Abstract Linkage-disequilibrium connects CX3CR1 V249I and T280M single-nucleotide polymorphisms; V249I occurs as a single-variant (SV) and T280M exclusively as a double-variant (DV) concurrent with V249I. The effect of these combined haplotypes remains unexplored in glioma. We identified CX3CR1 haplotypes in internal LGG and TCGA GBM cohorts and analyzed median overall survival (mOS). The proportion of each haplotype in glioma and normal patients was assessed via meta-analysis. Bulk RNAseq analysis was conducted in TCGA and internal GBM cohorts and scRNAseq in internal IDH mutant gliomas. In LGG, SV improved mOS (n=14, 21.03yrs) by twofold compared to WT (n=45, 9.41yrs) and DV (n=31, 10.49yrs; p=0.037). In TCGA GBM, SV (n=69, 15.65mo) improved mOS over DV (n=106, mOS 11.74mo; p=0.044). In combined meta-analysis, SV patients had increased risk for glioma development (OR 1.11, 1.03-1.19 p = 0.006) and the WT genotype was protective (OR 0.95, p=0.048). Collagen genes associated with increased immunosuppression (COL6A3: log2FC=2.33, p-adj=0.004; COL6A2: log2FC=1.55, p-adj=.059) were reduced in SV. MME, an endopeptidase associated with radiation resistance, was downregulated in SV (log2FC=3.29, p-adj=2.53e-6). MN1, associated with improved glioma survival, was upregulated in SV (log2FC=-1.76, p-adj=0.001). CCL18, an immunosuppressive chemokine associated with M2 macrophage polarization was reduced in SV (log2FC=2.36, p-adj=0.014). Thus, concomitant with its improved survival, SV is biologically distinct from DV and WT. Using scRNAseq, myeloid-derived cells (microglia/macrophages; 7758 cells) were re-clustered, identifying fourteen clusters. Cells clustered by CX3CR1 status, with 58.2% of SV cells in cluster five and 84.9% of DV cells in clusters six or seven. Cluster five over-expressed IL1B (average-log2FC 3.16), a tumor-suppressive M1 macrophage marker. Clusters six and seven were characterized by IFIT genes (IFIT3 average-log2FC 2.72 and 2.16 respectively), which corresponds to glioma associated microglia from recent scRNAseq microglial atlases. We demonstrate that CX3CR1 SV has improved survival and reduced immunosuppression over wildtype and this is lost with in the linked CX3CR1 DV genotype.

EPCO-04. H3F3A K27M MUTATION DRIVES A REPRESSIVE TRANSCRIPTOME VIA REDUCED SERINE 31 PHOSPHORYLATION BY MODULATING CHROMATIN ACCESSIBILITY, INDEPENDENT OF H3K27ME3 IN DIFFUSE MIDLINE GLIOMA

Abstract Heterozygous H3.3 K27M mutations are central to the pathogenesis of diffuse midline gliomas (DMG), causing a global reduction in H3K27 trimethylation (H3K27me3) and subsequent epigenetic dysregulation. H3.3 contains a unique Serine 31 (S31) phosphorylation site crucial for mitotic checkpoint regulation. In DMG cells, reduced mitotic S31 phosphorylation correlates with chromosomal instability and aneuploidy. Using a mouse model, we demonstrate that both H3.3K27M and H3.3S31A mutations promote high-grade glioma development, whereas wild-type H3.3 does not. Importantly, S31A, which maintains normal K27me, suggests that S31 phosphorylation loss alone is oncogenic. The H3.3K27M mutation disrupts epigenetic regulation by inhibiting the Polycomb Repressive Complex 2 (PRC2), leading to decreased H3K27me3 and unintended gene induction. Concurrently, K27M exerts a compensatory repressive effect on the transcriptome, mediated by reduced S31 phosphorylation, independent of PRC2 activity. Using CRISPR-engineered isogenic DMG cells and analyzing the transcriptome and chromatin accessibility with RNA-seq and ATAC-seq, we found that the K27M mutation produces a balanced gene expression profile, while PRC2 loss primarily leads to gene induction. Notably, cells with S31A mutations also maintain this balanced profile, linking the PRC2-independent effect of K27M to reduced S31 phosphorylation. Conversely, cells with wild-type K27 but S31A mutation show a repressive genomic state, evidenced by an up/down gene ratio of 0.75, owing to functional PRC2. We further show that the genes uniquely dysregulated by K27M or S31A, independent of PRC2, overlap significantly, with dysregulated genes displaying altered chromatin accessibility. This suggests that the effect of K27M and S31A mutations on gene regulation is primarily due to changes in chromatin state. This complex interplay points to targeting K27M-associated pathways, particularly S31 phosphorylation, as a promising therapeutic avenue in DMG, a malignancy with fewer effective treatments and dismal prognosis.

STEM-01. SHARED ASTROCYTE-LIKE GLIOMA STEM CELLS DRIVE HETEROGENEITY AND IMMUNE DYNAMICS IN ADULT-TYPE DIFFUSE GLIOMAS

Abstract Adult-type diffuse gliomas present significant treatment challenges due to their complex cellular composition and evolving nature. Understanding this heterogeneity is critical for the development of effective, targeted therapies. We conducted single-cell and single-nucleus RNA sequencing on a unique cohort of 66 tumours (single surgery) and 54 paired samples (two surgeries). This comprehensive dataset of approximately 900,000 cells allows us to dissect conserved cellular landscapes and dynamic evolution across diverse glioma subtypes. Using a novel phylogeny-based approach, we identified an astrocyte-like glioma stem cell (GSC) as the root of diverse glioma lineages. This discovery transforms our understanding of glioma development, pinpointing the GSC as a potential therapeutic target. The GSC’s similarity to healthy adult neural stem cells provides clues as to the origin of glioma heterogeneity and the shared basis of intratumoural diversity. Our analysis uncovered a shared cellular architecture across astrocytomas, oligodendrogliomas, and glioblastomas (GBMs). This architecture encompasses seven recurring malignant cell states: neuro-, oligo-, neuro-oligo-lineage, cycling (G1/S, G2/M), hypoxia-associated, and a quiescent astrocyte-like GSC. Importantly, these cell state proportions vary significantly between glioma subtypes. Additionally, we demonstrate that GBMs display substantially higher T-cell and myeloid cell infiltration than IDH-mutant gliomas. Counterintuitively, this correlates with a poorer prognosis, implying profound T-cell dysfunction and intricate myeloid cell-tumour interactions. Longitudinal analysis further highlights the dynamic nature of glioma cell populations and the immune landscape. Subtype-specific T-cell and myeloid gene expression profiles were identified, including potential targets such as PARD6G (GBM) and CXCL13 (IDH-mutant-astrocytoma), laying the groundwork for tailored immunotherapies and prognostic biomarkers. This study presents a comprehensive model of glioma heterogeneity and evolution. The model reveals a shared astrocyte-like GSC that fuels cellular diversity, coupled with distinct, dynamic immune landscapes in different glioma subtypes. These findings hold extraordinary potential for developing transformative treatment strategies. Future research functionally validating the GSC and its impact on tumour dynamics will be essential for translating these insights into improved patient outcomes.

Micro-biosensor fabrication by microfluidic channel for simultaneous detection of choline and creatine

Choline, and creatine are two common metabolites in the nervous system, and dysregulation in choline and creatine levels is associated with the development and recurrence of glioma. In this paper, we developed an enzymatic micro-biosensor for real-time combined sensing of choline and creatine. We simulated the influence of enzyme layer thickness and electrode spacing on the electrode work with COMSOL software, then employed microfluidic channels to immobilize an enzyme layer with a precise extent. And the sensor worked with this technique to transfer and pattern choline oxidase (ChOx) and the mixture of creatinase (Cr) and sarcosine oxidase (SO) onto targeted sites on microelectrode arrays (MEA). The combined sensing micro-biosensor was confirmed that it has high sensitivity for choline and creatine with 208 and 35 μA mM−1 cm−2, respectively, and also low detection limits to around 1 and 10 μM, respectively, with relative rapid response times within 10 s (≤10 s). This work demonstrates that microfluidic channels can be an efficient method for fabricating multi-analyte enzymatic micro-biosensor.

Bibliometric and visualization analysis in the field of epigenetics and glioma (2009-2024).

Glioma represents the most prevalent primary malignant tumor in the central nervous system, a deeper understanding of the underlying molecular mechanisms driving glioma is imperative for guiding future treatment strategies. Emerging evidence has implicated a close relationship between glioma development and epigenetic regulation. However, there remains a significant lack of comprehensive summaries in this domain. This study aims to analyze epigenetic publications pertaining to gliomas from 2009 to 2024 using bibliometric methods, consolidate the extant research, and delineate future prospects for investigation in this critical area. For the purpose of this study, publications spanning the years 2009 to 2024 were extracted from the esteemed Web of Science Core Collection (WoSCC) database. Utilizing advanced visualization tools such as CiteSpace and VOSviewer, comprehensive data pertaining to various aspects including countries, authors, author co-citations, countries/regions, institutions, journals, cited literature, and keywords were systematically visualized and analyzed. A thorough analysis was conducted on a comprehensive dataset consisting of 858 publications, which unveiled a discernible trend of steady annual growth in research output within this specific field. The nations of the United States, China, and Germany emerged as the foremost contributors to this research domain. It is noteworthy that von Deimling A and the Helmholtz Association were distinguished as prominent authors and institutions, respectively, in this corpus of literature. A rigorous keyword search and subsequent co-occurrence analysis were executed, ultimately leading to the identification of seven distinct clusters: "epigenetic regulation", "DNA repair", "DNA methylation", "brain tumors", "diffuse midline glioma (DMG)", "U-87 MG" and "epigenomics". Furthermore, an intricate cluster analysis revealed that the primary foci of research within this field were centered around the exploration of glioma pathogenesis and the development of corresponding treatment strategies. This article underscores the prevailing trends and hotspots in glioma epigenetics, offering invaluable insights that can guide future research endeavors. The investigation of epigenetic mechanisms primarily centers on DNA modification, non-coding RNAs (ncRNAs), and histone modification. Furthermore, the pursuit of overcoming temozolomide (TMZ) resistance and the exploration of diverse emerging therapeutic strategies have emerged as pivotal avenues for future research within the field of glioma epigenetics.

Gene Expression Profiling Regulated by lncRNA H19 Using Bioinformatic Analyses in Glioma Cell Lines.

Glioma, the most common type of primary brain tumor, is characterized by high malignancy, recurrence, and mortality. Long non-coding RNA (lncRNA) H19 is a potential biomarker for glioma diagnosis and treatment due to its overexpression in human glioma tissues and its involvement in cell division and metastasis regulation. This study aimed to identify potential therapeutic targets involved in glioma development by analyzing gene expression profiles regulated by H19. To elucidate the role of H19 in A172 and U87MG glioma cell lines, cell counting, colony formation, and wound healing assays were conducted. RNA-seq data analysis and bioinformatics analyses were performed to reveal the molecular interactions of H19. Cell-based experiments showed that elevated H19 levels were related to cancer cell survival, proliferation, and migration. Bioinformatics analyses identified 2,084 differentially expressed genes (DEGs) influenced by H19 which are involved in cancer progression. Specifically, ANXA5, CLEC18B, RAB42, CXCL8, OASL, USP18, and CDCP1 were positively correlated with H19 expression, while CSDC2 and FOXO4 were negatively correlated. These DEGs were predicted to function as oncogenes or tumor suppressors in gliomas, in association with H19. These findings highlight H19 and its associated genes as potential diagnostic and therapeutic targets for gliomas, emphasizing their clinical significance in patient survival.

Modulation of the Immune Environment in Glioblastoma by the Gut Microbiota

Studies increasingly support the role of the gut microbiota in glioma development and treatment, although the exact mechanisms remain unclear. Research indicates that the gut microbiota can influence glioma progression, response to therapies, and the effectiveness of treatments like immunotherapy, with certain microbial compositions being linked to better outcomes. Additionally, the gut microbiota impacts the tumor microenvironment, affecting both tumor growth and the response to treatment. This review will explore glioma, the gut microbiota, and how their interaction shapes glioma development and therapy responses. Additionally, this review examines the influence of gut microbiota metabolites, such as short-chain fatty acids (SCFAs) and tryptophan, on glioma development and treatment. It also explores gut microbiome signaling via pattern recognition receptors, and the role of molecular mimicry between microbial and tumor antigens in glioblastoma, and if these interactions affect glioma development and treatment.

Mitochondrial DNA Alterations in Glioblastoma and Current Therapeutic Targets.

Metabolic reprogramming within tumor cells involves a shift towards either glycolysis or mitochondrial respiration, depending on the stage of tumor progression. Consequently, irreversible dysfunction of the mitochondria is considered a crucial mechanism driving the progression mechanism. While numerous mutations in mitochondrial DNA (mtDNA) have been identified across various tumor types, including glioblastoma, many studies have been limited in the scope, focusing on small segments of mtDNA or utilizing sequencing methods with restricted sensitivity. As a result, several potentially significant mtDNA mutations may have been underestimated, along with their heteroplasmic states, which play a crucial role in determining the phenotypic impact of mtDNA mutation. Although both somatic and germline mtDNA mutations have been observed in different tumor types, research on the mtDNA mutations linked to glioblastoma remains scarce. The mitochondrial genome encodes thirteen protein-coding genes that are essential for the proper functioning of respiratory complex chains. Alterations in mitochondrial function manifest at various levels, including structural and functional changes, impacting mitogenic, hemodynamic, bioenergetic, and apoptotic signaling pathways. These alterations often signify a reduced efficiency of the oxidative phosphorylation system and energy production in tumor cells. As the crucial role of mitochondrial dysfunction in glioma development grows, mitochondria have emerged as promising targets for therapy aimed at overcoming chemoresistance and eliminating cancer cells. This brief review outlines the association between mtDNA alteration and glioblastoma, as well as the current advancements in therapeutic strategies targeting mtDNA alterations.

Metabolism: an important player in glioma survival and development.

Gliomas are malignant tumors originating from both neuroglial cells and neural stem cells. The involvement of neural stem cells contributes to the tumor's heterogeneity, affecting its metabolic features, development, and response to therapy. This review provides a brief introduction to the importance of metabolism in gliomas before systematically categorizing them into specific groups based on their histological and molecular genetic markers. Metabolism plays a critical role in glioma biology, as tumor cells rely heavily on altered metabolic pathways to support their rapid growth, survival, and progression. Dysregulated metabolic processes, involving carbohydrates, lipids, and amino acids not only fuel tumor development but also contribute to therapy resistance and metastatic potential. By understanding these metabolic changes, key intervention points, such as mutations in genes like RTK, EGFR, RAS, and IDH can be identified, paving the way for novel therapeutic strategies. This review emphasizes the connection between metabolic pathways and clinical challenges, offering actionable insights for future research and therapeutic development in gliomas.

Enhancing glioma treatment with 3D scaffolds laden with upconversion nanoparticles and temozolomide in orthotopic mouse model.

Targeted drug delivery for primary brain tumors, particularly gliomas, is currently a promising approach to reduce patient relapse rates. The use of substitutable scaffolds, which enable the sustained release of clinically relevant doses of anticancer medications, offers the potential to decrease the toxic burden on the patient's organism while also enhancing their quality of life and overall survival. Upconversion nanoparticles (UCNPs) are being actively explored as promising agents for detection and monitoring of tumor growth, and as therapeutic agents that can provide isolated therapeutic effects and enhance standard chemotherapy. Our study is focused on the feasibility of constructing scaffolds using methacrylated hyaluronic acid with additional impregnation of UCNPs and the chemotherapeutic drug temozolomide (TMZ) for glioma treatment. The designed scaffolds have been demonstrated their efficacy as a drug and UCNPs delivery system for gliomas. Using the aggressive orthotopic glioma model in vivo, it was found that the scaffolds possess the capacity to ameliorate neurological disorders in mice. Moreover, upon intracranial co-implantation of the scaffolds and glioma cells, the constructs disintegrate into distinct segments, augmenting the release of UCNPs into the surrounding tissue and concurrently reducing postoperative damage to brain tissue. The use of TMZ in the scaffold composition contributed to restraining glioma development and the reduction of tumor invasiveness. Our findings unveil promising prospects for the application of photopolymerizable biocompatible scaffolds in the realm of neuro-oncology.

Complement factor H is an ICOS ligand modulating Tregs in the glioma microenvironment.

The survival rate of glioma patients has not significantly increased in recent years despite aggressive treatment and advances in immunotherapy. The limited response to treatments is partially attributed to the immunosuppressive tumor microenvironment, where regulatory T cells (Tregs) play a pivotal role in immunological tolerance. In this study, we investigated the impact of complement factor H (FH) on Tregs within the glioma microenvironment and found that FH is an ICOS ligand. The binding of FH to this immune checkpoint molecule promoted the survival and function of Tregs and induced the secretion of TGF-beta (TGF-β) and IL-10, while also suppressing T-cell proliferation. We further demonstrated that cancer cells in human and mouse gliomas directly produce FH. Database investigations revealed that upregulation of FH expression was associated with the presence of Tregs and correlated with worse prognosis for glioma patients. We confirmed the effect of FH on glioma development in a mouse model, where FH knockdown was associated with decrease in number of ICOS+ Tregs and demonstrated a tendency of prolonged survival (p=0.064). Since the accumulation of Tregs represents a promising prognostic and therapeutic target, evaluating FH expression should be considered when assessing the effectiveness of and resistance to immunotherapies against glioma.

Bioinformatic Characterization of the Functional and Structural Effect of Single Nucleotide Mutations in Patients with High-Grade Glioma.

Background: Gliomas are neoplasms of the central nervous system that originate in glial cells. The genetic characteristics of this type of neoplasm are the loss of function of tumor suppressor genes such as TP53 and somatic mutations in genes such as IDH1/2. Additionally, in clinical cases, de novo single nucleotide polymorphisms (SNP) are reported, of which their pathogenicity and their effects on the function and stability of the protein are known. Methodology: Non-synonymous SNPs were analyzed for their structural and functional effect on proteins using a set of bioinformatics tools such as SIFT, PolyPhen-2, PhD-SNP, I-Mutant 3.0, MUpro, and mutation3D. A structural comparison between normal and mutated residues for disease-associated coding SNPs was performed using TM-aling and the SWISS MODEL. Results: A total of 13 SNPs were obtained for the TP53 gene, 1 SNP for IDH1, and 1 for IDH2, which would be functionally detrimental and associated with disease. Additionally, these changes compromise the structure and function of the protein; the A161S SNP for TP53 that has not been reported in any databases was classified as detrimental. Conclusions: All non-synonymous SNPs reported for TP53 were in the region of the deoxyribonucleic acid (DNA) binding domain and had a great impact on the function and stability of the protein. In addition, the two polymorphisms detected in IDH1 and IDH2 genes compromise the structure and activity of the protein. Both genes are related to the development of high-grade gliomas. All the data obtained in this study must be validated through experimental approaches.

MiR-155-5p regulates autophagy and apoptosis of glioma cells through RICTOR.

Glioma characterized by the high degree of drug resistance and the poor prognosis is the most common primary malignant tumors of the brain. And miRNA is involved in a variety of biological behaviors of tumors, enhancing or inhibiting the occurrence and development of tumors. Therefore, the present study aims to explore whether miR-155-5p can regulate autophagy and apoptosis of glioma through RICTOR. The significantly differential gene miR-155-5p was identified from the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo) databases GSE165937 and GSE138764 using bioinformatics analysis, and its expression was validated by quantitative real-time polymerase chain reaction (qRT-PCR). The putative target genes of miR-155-5p were predicted through interrogation of relevant databases, followed by identification of key target genes. Subsequently, core target genes were selected for functional enrichment analysis. The U87MG cell line was utilized as the experimental model and divided into Negative Control1 (NC1) group, Mimic group, Negative Control2 (NC2) group, Inhibitor group, and NC + 3-methyladenine (3-MA) group. The expression levels of miR-155-5p, RICTOR, P62, LC-3, Bax, Bcl-2, and Caspase-3 were assessed using qRT-PCR, cellular fluorescence imaging, and Western blotting; while apoptosis in the U87MG cell line was evaluated via flow cytometry. The results showed that miR-155-5P was highly expressed in glioma cells, which could inhibit the expression of Bax, Caspase-3, LCII/LCI and Beclin-1, and increase the expression of Bcl2 and P62. Flow cytometry and cell fluorescence were used to verify the above results. Moreover, when U87MG cells treated with miR-155-5p inhibitor were inhibited by 3-MA, the results showed that miR-155-5p enhanced the anti-apoptotic ability of U87MG cells by regulating autophagy. In addition, the bioinformatics results show that miR-155-5p survival prognosis in glioma into a strong negative correlation, while the survival prognosis of RICTOR in glioma showed a strong positive correlation. The core target genes Kyoto Encyclopedia of Genes and Genomes (KEGG) mainly occurred in PI3K-AKT signaling pathway; in addition, qRT-PCR and Western blot confirmed the regulatory effect of miR-155-5P on RICTOR. MiR-155-5p regulates autophagy and apoptosis-related proteins in glioma cells through RICTOR, affecting the occurrence and development of glioma.

Autophagy-associated biomarkers ULK2, UVRAG, and miRNAs miR-21, miR-126, and miR-374: Prognostic significance in glioma patients.

As the pioneering study from Pakistan, our research distinctly focuses on validating the roles of autophagy-associated genes and MicroRNAs (miRs) in the unique context of our population for glioma prognosis. The study delves into the nuanced interplay of autophagy within a miR-modulated environment, prompting an exploration of its potential impact on glioma development and survival. Employing real-time PCR (qPCR), we meticulously assessed the expression profiles of autophagy genes and miRs in glioma tissues, complemented by immunohistochemistry on Formalin-fixed paraffin-embedded tissues from the same patients. Our comprehensive statistical analyses, including the data normality hypothesis Shapiro-Wilk test, the Mann-Whitney U-test, Spearman correlation test, and Kaplan-Meier survival analysis, were tailored to unravel the intricate associations specific to low- and high-grade glioma within our population. Clinicopathological analysis revealed a predominance of male patients (66%) with a median age of 35 years. Glioblastoma (32%) and Astrocytoma (36%) were the most prevalent histopathological subtypes. Molecular analysis showed significant correlations between prognostic markers (Ki-67, IDH-1, p53) and clinicopathological factors, including age, histological type, radiotherapy, and chemotherapy. In high-grade glioma, increased expression of AKT and miR-21, coupled with reduced ULK2 and LC3 expression was distinctly observed. While correlation analysis identified a strong positive correlation between ULK2 and UVRAG, PTEN, miR-7, and miR-100 in low-grade glioma, unveiling distinctive molecular signatures unique to our study. Furthermore, a moderate positive correlation emerged between ULK2 and mTOR, miR-7, miR-30, miR-100, miR-204, and miR-374, also between miR-21 and miR-126. Similarly, a positive correlation appeared between ULK2 and AKT, LC3, PI3K, PTEN, ULK1, VPS34, mTOR, Beclin1, UVRAG, miR-7 and miR-374. AKT positively correlated with LC3, PI3K, PTEN, ULK1, VPS34, mTOR, Beclin1, UVRAG, miR-7, miR-30, miR-204, miR-374, miR-126 and miR-21 weakly correlated with AKT and miR-30 in high-grade glioma, providing further insights into the autophagy pathway within our population. The enrichment analysis for miR-21, miR-126, and miR-374 showed MAPK pathway as a common pathway along with Ras, PI3K, and mTOR pathway. The low ULK2, UVRAG, and miR-374 expression group exhibited significantly poor overall survival in glioma, while miR-21 over-expression indicated a poor prognosis in glioma patients, validating it in our population. This study provides comprehensive insights into the molecular landscape of gliomas, highlighting the dysregulation of autophagy genes ULK2, and UVRAG and the associated miR-21, miR-126 and miR-374 as potential prognostic biomarkers and emphasizing their unique significance in shaping survival outcomes in gliomas within the specific context of the Pakistani population.

The role of PTPN11 in MAPK/ERK signaling pathway and its impact on the occurrence and development of glioma

The protein tyrosine phosphatase, PTPN11, exerts a crucial inhibitory influence on the MAPK/ERK signaling cascade. This research endeavored to unravel the involvement of PTPN11 in the initiation and progression of glioma, as well as its underlying molecular interactions. To achieve this, Western blotting was employed to observe alterations in ERK phosphorylation upon PTPN11 depletion or amplification. Furthermore, immunoprecipitation coupled with mass spectrometry was utilized to pinpoint the targets of PTPN11's enzymatic activity. The outcomes demonstrated that the absence of PTPN11 significantly enhanced ERK phosphorylation, whereas an excess of the protein had the converse effect. In-depth explorations into the molecular mechanisms highlighted that PTPN11's inhibitory action is chiefly executed through the deactivation of Ras proteins by dephosphorylation. These revelations accentuate the critical part played by PTPN11 within the MAPK/ERK pathway in relation to glioma development and offer insights that could lead to innovative treatments for this disease.

Machine learning-based discovery of UPP1 as a key oncogene in tumorigenesis and immune escape in gliomas.

Gliomas are the most common and aggressive type of primary brain tumor, with a poor prognosis despite current treatment approaches. Understanding the molecular mechanisms underlying glioma development and progression is critical for improving therapies and patient outcomes. The current study comprehensively analyzed large-scale single-cell RNA sequencing and bulk RNA sequencing of glioma samples. By utilizing a series of advanced computational methods, this integrative approach identified the gene UPP1 (Uridine Phosphorylase 1) as a novel driver of glioma tumorigenesis and immune evasion. High levels of UPP1 were linked to poor survival rates in patients. Functional experiments demonstrated that UPP1 promotes tumor cell proliferation and invasion and suppresses anti-tumor immune responses. Moreover, UPP1 was found to be an effective predictor of mutation patterns, drug response, immunotherapy effectiveness, and immune characteristics. These findings highlight the power of combining diverse machine learning methods to identify valuable clinical markers involved in glioma pathogenesis. Identifying UPP1 as a tumor growth and immune escape driver may be a promising therapeutic target for this devastating disease.

Regulation of a novel circATP8B4/miR-31-5p/nestin ceRNA crosstalk in proliferation, motility, invasion and radiosensitivity of human glioma cells.

Deregulation of circular RNAs (circRNAs) is frequent in human glioma. Although circRNA ATPase phospholipid transporting 8B4 (circATP8B4) is highly expressed in glioma, its precise action in glioma development is still not fully understood. The relationship of microRNA (miR)-31-5p and circATP8B4 or nestin (NES) was predicted by bioinformatic analysis and confirmed by RNA pull-down and Dual-luciferase reporter assays. CircATP8B4, miR-31-5p and NES were quantified by qRT-PCR or western blot. Cell functional behaviors were assessed by EdU, wound-healing and transwell invasion assays. Xenograft model experiments were performed to define circATP8B4's activity in vivo. CircATP8B4, a true circular transcript, was upregulated in human glioma. CircATP8B4 downregulation weakened glioma cell growth, motility, and invasion and facilitated radiosensitivity. Mechanistically, circATP8B4 and NES 3'UTR harbored a shared miR-31-5p pairing site, and circATP8B4 involved the post-transcriptional NES regulation by functioning as a competing endogenous RNA (ceRNA). Furthermore, the miR-31-5p/NES axis participated in circATP8B4's activity in glioma cell proliferation, motility, invasion and radiosensitivity. Additionally, circATP8B4 loss diminished tumor growth and enhanced the anticancer effect of radiotherapy in vivo. We have uncovered an uncharacterized ceRNA cascade, circATP8B4/miR-31-5p/NES axis, underlying glioma development and radiosensitivity. Targeting the ceRNA crosstalk may have potential to improve the outcome of glioma patients.

Retracted] Jumonji AT‑rich interactive domain 1B overexpression is associated with the development and progression of glioma

Retracted] Jumonji AT‑rich interactive domain 1B overexpression is associated with the development and progression of glioma