Glioma Development Research Articles

PSMC2 promotes glioma progression by regulating immune microenvironment and PI3K/AKT/mTOR pathway

BackgroundGlioma, the most frequent and malignant central nervous system (CNS) cancer, has a bad outcome. Proteasome 26S subunit ATPase 2 (PSMC2) is an essential part of the 26S proteasome and promotes the development of several tumors. However, the pathway and function of PSMC2 in glioma have not been unelucidated. MethodsThis study analyzed PSMC2 expression in glioma tissues and its predictive significance for patients. We examined the link between PSMC2 and DNA methylation, immune cell infiltration, tumor immune cycle, immune cell homeostasis, and immune checkpoints. Subsequently, immunohistochemistry and in vitro trials were employed to validate the expression, prognostic potential, and function of PSMC2 in glioma. The mechanisms of PSMC2 in glioma were further explored. ResultsOur study revealed that PSMC2 expression increased in glioma tissues contrasted with healthy tissues, and patients with high PSMC2 glioma exhibited poor overall survival (OS) compared to the low-PSMC2 group. Immune profile analysis revealed that PSMC2 was positively related to immunosuppressive cell infiltration and immune checkpoints and adversely related to the cancer immune cycle and immune cell homeostasis. In cell-based investigations, the inhibition of PSMC2 was found to effectively suppress the aggressiveness and proliferation of glioma cell lines while also enhancing cell cycle arrest and promoting cell death. Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and in vitro experiments showed that PSMC2 promoted glioma development through the PI3K/AKT/mTOR pathway. ConclusionsPSMC2 was upregulated in glioma and promoted cancer progression by modulating the tumor immune microenvironment, cancer cell biological behavior, immune cell homeostasis, and the PI3K/AKT/mTOR pathway, providing a new option to treat glioma.

PSMA2 promotes glioma proliferation and migration via EMT

BackgroundGliomas advance rapidly and are associated with a poor prognosis. Epithelial-mesenchymal transition (EMT) accelerates the progression of gliomas, exerting a pivotal role in glioma development. Proteasome subunit alpha type-2 (PSMA2) exhibits high expression levels in gliomas. however, its specific involvement in glioma progression and its correlation with EMT remain elusive. This study aims to elucidate the role of PSMA2 in glioma progression and its potential association with EMT. MethodsOnline tools were employed to analyze the expression patterns and survival curves of PSMA2 in gliomas. The relationship between PSMA2 and various characteristics of glioma patients was investigated using data from the TCGA and CGGA databases. In vitro, cell proliferation and migration were assessed through CCK-8, colony formation, and transwell assays. Furthermore, a tumor xenograft model in nude mice was established to evaluate in vivo tumorigenesis. Protein binding to PSMA2 was scrutinized using co-immunoprecipitation MS (co-IP MS). The potential biological functions and molecular pathways associated with PSMA2 were explored through GO analysis and KEGG analysis, and the correlation between PSMA2 and EMT was validated through correlation analysis and Western blot experiments. ResultsBioinformatics analysis revealed a significant upregulation of PSMA2 across various cancers, with particularly heightened expression in gliomas. Moreover, elevated PSMA2 levels were correlated with advanced tumor stages and diminished survival rates among glioma patients. Inhibition of PSMA2 demonstrated a pronounced suppressive effect on glioma cell proliferation, both in vitro and in vivo. Knockdown of PSMA2 also impeded the migratory capacity of glioma cells. GO and KEGG enrichment analyses indicated that PSMA2-binding proteins (identified through Co-IP-MS) were associated with cell adhesion molecule binding and cadherin binding. Western blot results further confirmed the role of PSMA2 in promoting epithelial-mesenchymal transition (EMT) in glioma cells. ConclusionOur study provides evidence supporting the role of PSMA2 as a regulatory factor in EMT and suggests its potential as a prognostic biomarker for glioma progression.

Abnormal expression of long non‑coding RNA LINC01270 in glioma and its correlation with X‑ray computed tomography signs.

This study focused on the association of LINC01270 and computed tomography (CT) signs with glioma development, to evaluate their potential in the early detection of glioma. Serum LINC01270 was evaluated in glioma patients and healthy individuals using PCR. The involvement of LINC01270 in glioma onset and development was evaluated by ROC and chi‑square test. The association of LINC01270 with the CT signs and their combined effects in the diagnosis in glioma were also estimated. Serum LINC01270 was significantly elevated in glioma patients, which was closely associated with patients' advanced WHO grades and lower KPS. Both LINC01270 upregulation and CT findings showed significant potential in diagnosing glioma, and LINC01270 correlated significantly with the invasion risk and metastasis indicated on CT. The combination of LINC01270 expression and CT findings significantly improved the sensitivity and specificity of glioma diagnosis. Upregulated LINC01270 in glioma is associated with malignant and severe disease development and has significant diagnostic value. Combined detection of LINC01270 and CT findings could improve the diagnostic efficacy in glioma cases, thus optimizing clinical diagnosis.

Abstract 4887: Unveiling the functional impact of glioma non-coding germline variants using large language models

Abstract Efforts to identify the risk for developing gliomas through Genome-Wide Association Studies (GWAS) face relevant challenges, such as accurately pinpointing the genomic positions of germline variants, primarily found in non-coding regions, with unclear functional implications in glioma development. In this context, the GET method, a large language model designed to unveil regulatory grammars across 213 human cell types, emerges as a valuable tool for elucidating the mechanisms of non-coding mutations. Our aims include: I) Validate the efficacy of the GET method using a well-documented case and prioritize relevant variants for analysis; II) Refine the genomic positions of these variants and exploring their linkage disequilibrium (LD); III) Identify potential motifs and genes that might be influenced by these high-impact variants. After examining published GWAS, 39 non-coding SNPs in gliomas were found. Adding 316 variants in high LD (R2 > 0.8) expanded the dataset to 355 variants for analysis. Using the GET method, we calculated impact scores (ISs) for each variant, considering changes in motif binding score (ΔBM) and motif gradient (GM) across human astrocytes. We focused on rare variants (risk allele frequency <0.25) with the higher odds ratios (OR). The table presents GET results for a well-known case-control, showing its role in increasing glioma risk through OCT4 motif disruption and enhanced MYC expression, as previously was confirmed experimentally. Moreover, it details results concerning the 5 rare germline variants exhibiting the highest ISs, including precise genomic positions and the most affected motifs and genes that could potentially be impacted by each variant. Using a large language model, this study overcomes the challenge of mere variant identification, aiming to establish a framework for uncovering the underlying mechanism of risk variants. While further validation is essential, this is a promising approach to explore the impact of germline mutations. Variant ID Genomic Position Altered Motif Affected Gene Ref allele Alt allele Case-control rs55705857 Chr8:129633445 OCT4+SOX2:POU MYC A G H-I variant #1 rs78378222 Chr17:7668433 HD/18 PER1 T G H-I variant #2 rs518394 Chr9:22019673 KLF/SP/2 CDKN2A G C H-I variant #3 rs79495512 Chr15:76199995 KLF/SP/2 LINGO1 T C H-I variant #4 rs78185702 Chr15:76317893 SMAD LINGO1 C T H-I variant #5 rs2538067 Chr7:54907724 CTCF EGFR G A Citation Format: Maria del Mar Alvarez-Torres, Xi Fu, Romella K Sagatelian, Alejandro L Buendia, Raul Rabadan. Unveiling the functional impact of glioma non-coding germline variants using large language models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4887.

Abstract 4370: Functional characterisation of a novel mutation in PRKCA, a major driver of chordoid gliomas

Abstract Chordoid gliomas (ChG) are a rare low-grade brain tumor, believed to be derived from tanycytes. An analysis by the team identified a novel mutation present in all ChGs: PRKCA p.D463H. This mutation involves a D463H substitution at the kinase domain of the Protein kinase C alpha (PKCα), it is not found in any other cancer, and represents the hallmark of ChG. The aim of the project is to identify novel and biologically relevant PKCαD463H signaling pathways, which will demonstrate the involvement and the role of this mutated kinase in cellular functions implicated in the development of ChGs. The D463H mutation affects a critical residue of the kinase domain of PKCα, suggesting that such a change modifies substrate affinity. Following the purification of PKCαD463H, we have shown its inactivation via in vitro kinase assays and peptide array. In cellulo fret-based activity reporter assays have shown that PKCαD463H has a dominant negative effect over PKCαWT. Through co-immunoprecipitation we have shown that the mutant protein can bind the WT form and also colocalizes in the cell. Our results also show that the mutation affects the tertiary structure of the protein, resulting in a more open, unstable protein compared to the WT. Phosphoproteomic analysis of HEK cells overexpressing PKC⍺D463H show a decrease of phosphorylation specifically on proteins involved with cell-cell adhesion, including functionally relevant phosphosites. This is in line with our Co-IP mass spectrometry data which shows a decrease in interaction of PKC⍺D463H with proteins involved in cell junctions. The cell of origin, tanycytes, are highly specialized cells that contain important cell-cell junctions and therefore their perturbation could be a potential route of tumorigenesis. By understanding these changes integrated with our snRNAseq and bulk RNAseq of ChGs, and exploration in cellular models, we hope to elucidate the mechanism by which the mutation leads to the development of Chordoid Glioma. Citation Format: Charlotte Bellamy, Hannah Tovell, Florent Dingli, Damarys Loew, Stephane Liva, Selina Schwaighofer, Eduard Stefan, Alexandra Newton, Marc Sanson, Franck Bielle. Functional characterisation of a novel mutation in PRKCA, a major driver of chordoid gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4370.

The construction of a novel prognostic prediction model for glioma based on GWAS-identified prognostic-related risk loci.

Glioma is a highly malignant brain tumor with a grim prognosis. Genetic factors play a role in glioma development. While some susceptibility loci associated with glioma have been identified, the risk loci associated with prognosis have received less attention. This study aims to identify risk loci associated with glioma prognosis and establish a prognostic prediction model for glioma patients in the Chinese Han population. A genome-wide association study (GWAS) was conducted to identify risk loci in 484 adult patients with glioma. Cox regression analysis was performed to assess the association between GWAS-risk loci and overall survival as well as progression-free survival in glioma. The prognostic model was constructed using LASSO Cox regression analysis and multivariate Cox regression analysis. The nomogram model was constructed based on the single nucleotide polymorphism (SNP) classifier and clinical indicators, enabling the prediction of survival rates at 1-year, 2-year, and 3-year intervals. Additionally, the receiver operator characteristic (ROC) curve was employed to evaluate the prediction value of the nomogram. Finally, functional enrichment and tumor-infiltrating immune analyses were conducted to examine the biological functions of the associated genes. Our study found suggestive evidence that a total of 57 SNPs were correlated with glioma prognosis (p < 5 × 10-5). Subsequently, we identified 25 SNPs with the most significant impact on glioma prognosis and developed a prognostic model based on these SNPs. The 25 SNP-based classifier and clinical factors (including age, gender, surgery, and chemotherapy) were identified as independent prognostic risk factors. Subsequently, we constructed a prognostic nomogram based on independent prognostic factors to predict individualized survival. ROC analyses further showed that the prediction accuracy of the nomogram (AUC = 0.956) comprising the 25 SNP-based classifier and clinical factors was significantly superior to that of each individual variable. We identified a SNP classifier and clinical indicators that can predict the prognosis of glioma patients and established a prognostic prediction model in the Chinese Han population. This study offers valuable insights for clinical practice, enabling improved evaluation of patients' prognosis and informing treatment options.

Abstract B033: Histone H3.3 K27M and G34R/V glioma driver mutations inhibit mitotic phosphorylation of H3.3 S31, driving tumor formation by inducing chromosomal instability

Abstract Diffuse gliomas are pediatric high-grade gliomas that frequently harbor heterozygous histone H3.3 K27M, G34R, or G34V mutations. These mutations alter histone methylations, although the precise mechanism(s) of gliomagenesis remains uncertain. H3.3 contains a unique Serine at position 31 that is phosphorylated in prophase and dephosphorylated in anaphase during normal cell division. Previously we have reported that chromosome missegregation triggers H3.3 S31 phosphorylation along chromosome arms in ana/telophase leading to p53-induced cell cycle arrest. Here we show, in vitro and in vivo, that H3.3 K27M, G34R, and G34V suppress S31 phosphorylation by its mitotic kinase, Chk1. In diploid cells, overexpression of H3.3 K27M, G34R, G34V, or non-phosphorylatable S31A significantly increases the frequency of chromosome missegregation, while H3.3 K36M did not. This missegregation phenotype could be rescued by overexpression of K27M/S31E or G34R/S31E double mutants. Next, we used CRISPR/Cas9 gene editing to revert K27M or G34V patient-derived DMG cells to WT or replace the mutant allele with S31A. Reversion to WT increased metaphase S31 phosphorylation and reduced chromosome missegregations, but inserting an S31A mutation caused more mitotic defects. Following a mitotic error, newly formed aneuploid cells overexpressing K27M, G34R, or G34V suppress p53 levels and continue to divide, while WT overexpressing cells always arrest. To test the effects of diminished S31 phosphorylation on gliomagenesis, we utilized a novel mouse model of glioma. Expression of PDGFß linked to H3.3K27M, H3.3G34R, and H3.3S31A in neural stem cells in vivo promoted the development of high-grade gliomas in under 100 days, whereas PDFß-H3.3WT did not. Notably, the S31A tumors had histologically normal levels of K27me3 and K36me3. This work shows that a single glioma-associated point mutation in H3.3 can generate chromosomal instability, and which is a major contributing factor to H3.3 K27M and G34-altered glioma formation. Citation Format: Charles A. Day, Florina Grigore, Alyssa Langfald, Faruck Hakkim, David Daniels, Kevin Vaughan, James Robinson, Edward Hinchcliffe. Histone H3.3 K27M and G34R/V glioma driver mutations inhibit mitotic phosphorylation of H3.3 S31, driving tumor formation by inducing chromosomal instability [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B033.

Abstract B039: Identification of sex-specific molecular features in glioma transcriptome

Abstract Glioma is a lethal disease with limited treatment options available. Sex differences in glioma are well-documented in clinical settings, with males having twice the risk of developing the disease and increased mortality compared to female counterparts. To investigate the molecular basis of sex differences in glioma, we analyzed transcriptomic sex differences in a collection of three independent glioma datasets and validated them in additional independent studies. The impact of differentially expressed genes were assessed through Gene Set Enrichment Analysis (GSEA) on approximately 5000 gene sets to interpret their biological relevance. Given the well-recognized heterogeneity of glioma, we also integrated three single-cell RNA (scRNA) sequencing datasets to decipher the sex differences in cellular composition and cell-type specific differential gene expression between male and female tumors. The effects of sex on gene expression are modest and primarily driven by the X chromosome (14 out of 16 differentially expressed genes were on the X chromosome). These genes are associated with escape from X-chromosome inactivation (e.g., KDM5C, KDM6A) and are also sex-differentially expressed (DE) in the healthy human brain according to Genotype-Tissue Expression (GTEx) data. GSEA results suggest increased activity in cell proliferation and neuronal signaling in male GBM samples, whereas females show enrichment in glycoprotein/lipid metabolism. By deconvoluting the cell-type composition, we identified a higher percentage of pericytes in the male glioma tumor microenvironment compared to those in females, which is consistent with recent spatial-omic discoveries in glioma. By integrating scRNA sequencing data, we found that both differentially expressed genes and pathways show cell-type-specific enrichment. For example, the female-biased gene GBGT1 is exclusively expressed in the myeloid lineage, while male-biased neuronal pathways are enriched in cancer stem cells. Integrating with the inference of cell trajectories, we observed that male tumors harbor more unconnected, invasive malignant cells than females, which might explain the poor prognosis in male glioma patients. In summary, our results provide a comprehensive multi-level characterization of sex differences in glioma tumors, and these findings will provide novel insights into glioma disease progression and development of new therapy. Citation Format: Yingbo Huang, Yuting Shan, Weijie Zhang, Christina Printzis, Lorenzo Pesce, Barbara Elaine Stranger, R. Stephanie Huang. Identification of sex-specific molecular features in glioma transcriptome [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B039.

MAD2L2 as a novel prognostic biomarker and its correlation with immune infiltrates in glioma

Background: The most common type of central nervous system tumor is glioma, the identification of Glioma biomarkers is essential. MAD2L2, which is abbreviated as MAD2-Like2, collaborates with a number of proteins to carry out numerous essential cellular functions. Uncertain is the role of MAD2L2 in glioma. The role of MAD2L2 expression is examined for the first time in relation to gliomas occurrence and development in this study Methods: A bioinformatics and clinicopathological analysis, immune infiltration analysis, and enrichment analysis were conducted based on TCGA and additional gene expression analysis. Using ssGSEA and TIMER, the immune response to MAD2L2 expression in glioma was analyzed statistically. This study also analyzed the effect of MAD2L2 overexpression on major chemotherapeutic medicines and the methylation status of glioma patients. CGGA, HPA data analysis, and K-M survival were also utilized to validate the results. Results: MAD2L2 was a crucial independent prognostic factor for glioma patients. Correlations were found between MAD2L2 expression and age, IDH status, WHO grades and 1p/19q codeletion. MAD2L2 is intimately connected to the DNA replication, transcription, cell cycle, immune system, and signal transduction pathways, as determined by the GSEA. In glioma, The majority of MAD2L2 DNA methylation sites were hypomethylated, and the degree of methylation was associated with patient outcomes. Chemotherapy would benefit MAD2L2 overexpression patients. according to these results. The expression of MAD2L2 was associated with partial immune cell infiltration and co-expressed with immune-related genes and immune checkpoints. Conclusion: Glioma is characterized by higher MAD2L2 expression, and high MAD2L2 expression is linked with a poor prognosis. MAD2L2 might participate in tumor development by regulating tumor-infiltrating cells inside the TME. MAD2L2 could possibly be an immunotherapeutic target.

IGF2BP2 modulates autophagy and serves as a prognostic marker in glioma.

Glioma, a malignant brain tumor originating from neural glial cells, presents significant treatment challenges. However, the underlying mechanisms of glioma development are not fully understood, and effective targets are lacking. This study provides insights into the role of insulin-like growth factor 2 messenger RNA-binding protein 2 (IGF2BP2) in glioma progression and its therapeutic potential. Our analysis illustrated that elevated IGF2BP2 expression associated with significantly shorter survival among patients with low-grade glioma (LGG)in The Cancer Genome Atlas (TCGA) database. IGF2BP2 depletion led to compromised cell viability, G0/G1 phase arrest, and reduced colony-formation ability. Furthermore, ultrastructural analysis and mCherry-GFP-LC3 reporter assay revealed an increased abundance of autophagosomes upon IGF2BP2 knockdown. Western blot analysis corroborated these findings by showing reduced p62 levels coupled with increased LC3-ІІ/LC3-I ratio upon IGF2BP2 knockdown. A multicolor immunohistochemistry assay demonstrated the positive correlation between IGF2BP2 and p62 expression in glioma patient samples. Additionally, our analysis suggested a link between IGF2BP2 expression and drug-resistant markers in TCGA-LGG samples, and Cell Counting Kit-8cell viability assay revealed that knockdown of IGF2BP2 sensitized cells to temozolomide treatment. This comprehensive exploration unveils the role of IGF2BP2 in glioma progression, shedding light on autophagy modulation and chemosensitization strategies for glioma therapy.

TGIF2 is a potential biomarker for diagnosis and prognosis of glioma.

TGFB-induced factor homeobox 2 (TGIF2), a member of the Three-Amino-acid-Loop-Extension (TALE) superfamily, has been implicated in various malignant tumors. However, its prognostic significance in glioma, impact on tumor immune infiltration, and underlying mechanisms in glioma development remain elusive. The expression of TGIF2 in various human normal tissues, normal brain tissues, and gliomas was investigated using HPA, TCGA, GTEx, and GEO databases. The study employed several approaches, including Kaplan-Meier analysis, ROC analysis, logistic regression, Cox regression, GO analysis, KEGG analysis, and GSEA, to explore the relationship between TGIF2 expression and clinicopathologic features, prognostic value, and potential biological functions in glioma patients. The impact of TGIF2 on tumor immune infiltration was assessed through Estimate, ssGSEA, and Spearman analysis. Genes coexpressed with TGIF2 were identified, and the protein-protein interaction (PPI) network of these coexpressed genes were constructed using the STRING database and Cytoscape software. Hub genes were identified using CytoHubba plugin, and their clinical predictive value was explored. Furthermore, in vitro experiments were performed by knocking down and knocking out TGIF2 using siRNA and CRISPR/Cas9 gene editing, and the role of TGIF2 in glioma cell invasion and migration was analyzed using transwell assay, scratch wound-healing assay, RT-qPCR, and Western blot. TGIF2 mRNA was found to be upregulated in 21 cancers, including glioma. High expression of TGIF2 was associated with malignant phenotypes and poor prognosis in glioma patients, indicating its potential as an independent prognostic factor. Furthermore, elevated TGIF2 expression positively correlated with cell cycle regulation, DNA synthesis and repair, extracellular matrix (ECM) components, immune response, and several signaling pathways that promote tumor progression. TGIF2 showed correlations with Th2 cells, macrophages, and various immunoregulatory genes. The hub genes coexpressed with TGIF2 demonstrated significant predictive value. Additionally, in vitro experiments revealed that knockdown and knockout of TGIF2 inhibited glioma cell invasion, migration and suppressed the epithelial-mesenchymal transition (EMT) phenotype. TGIF2 emerges as a potential biomarker for glioma, possibly linked to tumor immune infiltration and EMT.

Exosomes in Glioma: Unraveling Their Roles in Progression, Diagnosis, and Therapy.

Gliomas, the most prevalent primary malignant brain tumors, present a challenging prognosis even after undergoing surgery, radiation, and chemotherapy. Exosomes, nano-sized extracellular vesicles secreted by various cells, play a pivotal role in glioma progression and contribute to resistance against chemotherapy and radiotherapy by facilitating the transportation of biological molecules and promoting intercellular communication within the tumor microenvironment. Moreover, exosomes exhibit the remarkable ability to traverse the blood-brain barrier, positioning them as potent carriers for therapeutic delivery. These attributes hold promise for enhancing glioma diagnosis, prognosis, and treatment. Recent years have witnessed significant advancements in exosome research within the realm of tumors. In this article, we primarily focus on elucidating the role of exosomes in glioma development, highlighting the latest breakthroughs in therapeutic and diagnostic approaches, and outlining prospective directions for future research.

Expression of overall survival-EMT-immune cell infiltration genes predict the prognosis of glioma

This study investigates the crucial role of immune- and epithelial-mesenchymal transition (EMT)-associated genes and non-coding RNAs in glioma development and diagnosis, given the challenging 5-year survival rates associated with this prevalent CNS malignant tumor. Clinical and RNA data from glioma patients were meticulously gathered from CGGA databases, and EMT-related genes were sourced from dbEMT2.0, while immune-related genes were obtained from MSigDB. Employing consensus clustering, novel molecular subgroups were identified. Subsequent analyses, including ESTIMATE, TIMER, and MCP counter, provided insights into the tumor microenvironment (TIME) and immune status. Functional studies, embracing GO, KEGG, GSVA, and GSEA analyses, unraveled the underlying mechanisms governing these molecular subgroups. Utilizing the LASSO algorithm and multivariate Cox regression, a prognostic risk model was crafted. The study unveiled two distinct molecular subgroups with significantly disparate survival outcomes. A more favorable prognosis was linked to low immune scores, high tumor purity, and an abundance of immune infiltrating cells with differential expression of non-coding RNAs, including miRNAs. Functional analyses illuminated enrichment of immune- and EMT-associated pathways in differentially expressed genes and non-coding RNAs between these subgroups. GSVA and GSEA analyses hinted at abnormal EMT status potentially contributing to glioma-associated immune disorders. The risk model, centered on OS-EMT-ICI genes, exhibited promise in accurately predicting survival in glioma. Additionally, a nomogram integrating the risk model with clinical characteristics demonstrated notable accuracy in prognostic predictions for glioma patients. In conclusion, OS-EMT-ICI gene and non-coding RNA expression emerges as a valuable indicator intricately linked to immune microenvironment dysregulation, offering a robust tool for precise prognosis prediction in glioma patients within the OBMRC framework.

Distinguishing IDH mutation status in gliomas using FTIR-ATR spectra of peripheral blood plasma indicating clear traces of protein amyloid aggregation

BackgroundGlioma is a primary brain tumor and the assessment of its molecular profile in a minimally invasive manner is important in determining treatment strategies. Among the molecular abnormalities of gliomas, mutations in the isocitrate dehydrogenase (IDH) gene are strong predictors of treatment sensitivity and prognosis. In this study, we attempted to non-invasively diagnose glioma development and the presence of IDH mutations using multivariate analysis of the plasma mid-infrared absorption spectra for a comprehensive and sensitive view of changes in blood components associated with the disease and genetic mutations. These component changes are discussed in terms of absorption wavenumbers that contribute to differentiation.MethodsPlasma samples were collected at our institutes from 84 patients with glioma (13 oligodendrogliomas, 17 IDH-mutant astrocytoma, 7 IDH wild-type diffuse glioma, and 47 glioblastomas) before treatment initiation and 72 healthy participants. FTIR-ATR spectra were obtained for each plasma sample, and PLS discriminant analysis was performed using the absorbance of each wavenumber in the fingerprint region of biomolecules as the explanatory variable. This data was used to distinguish patients with glioma from healthy participants and diagnose the presence of IDH mutations.ResultsThe derived classification algorithm distinguished the patients with glioma from healthy participants with 83% accuracy (area under the curve (AUC) in receiver operating characteristic (ROC) = 0.908) and diagnosed the presence of IDH mutation with 75% accuracy (AUC = 0.752 in ROC) in cross-validation using 30% of the total test data. The characteristic changes in the absorption spectra suggest an increase in the ratio of β-sheet structures in the conformational composition of blood proteins of patients with glioma. Furthermore, these changes were more pronounced in patients with IDH-mutant gliomas.ConclusionsThe plasma infrared absorption spectra could be used to diagnose gliomas and the presence of IDH mutations in gliomas with a high degree of accuracy. The spectral shape of the protein absorption band showed that the ratio of β-sheet structures in blood proteins was significantly higher in patients with glioma than in healthy participants, and protein aggregation was a distinct feature in patients with glioma with IDH mutations.

Practice of neural homeostasis theory in the treatment of glioma

Glioma is the most common primary malignant brain tumor in adults. It is resistant to traditional treatments or tends to invade brain functional areas. The current treatment options often lead to high rates of disability or mortality, emphasizing the urgent need for new therapies and approaches. Neurohomeostasis, which is responsible for maintaining normal physiological functions in body, plays a critical role in the development and progression of glioma. In the clinical management of glioma, it is important not only to target the tumor cells but also to address the neurohomeostatic imbalances before, during, and after surgery, for achieving better treatment outcomes. The exploration, development, and application of the neurohomeostasis theory in glioma treatment have the potential to develop current diagnostic and therapeutic strategies, offering new perspectives for the clinical management of this condition.

PBX3 as a biomarker for the early diagnosis and prediction of prognosis of glioma.

Increasing evidence have elucidated that PBX3 played a crucial role in cancer initiation and progression. PBX3 was differentially expressed in many cancer types. However, PBX3 potential involvement in gliomas remains to be explored. The expression level of PBX3 in glioma tissues and glioma cells, and its correlation with clinical features were analyzed by data from TCGA, GEPIA, CGGA and CCLE. Univariable survival and Multivariate Cox analysis was used to compare several clinical characteristics with survival. We also analyzed the correlation between PBX3 expression level and survival outcome and survival time of LGG and GBM patients by using linear regression equation. GSEA was used to generate an ordered list of all genes related to PBX3 expression and screening of genes co-expressed with PBX3 mRNA by "limma" package. The results showed that PBX3 was highly expressed in gliomas and its expression increased with the increase of malignancy. Survival analysis found that PBX3 is more valuable in predicting the OS and PFI of LGG patients than that of GBM. For further study, TCGA and CGGA data were downloaded for univariate Cox analysis and multivariate Cox analysis which showed that the expression of PBX3 was independent influencing factors for poor prognosis of LGG patients. Meanwhile, Receiver operating characteristic (ROC) curve showed that PBX3 was a predictor of overall survival rate and progression-free survival rate of LGG. Linear regression model analysis indicated that the higher expression of PBX3 the higher the risk of death of LGG patients, and the higher expression of PBX3 the higher the risk of disease progression of LGG patients. Next, TCGA data were downloaded for GSEA and Co-expression analyses, which was performed to study the function of PBX3. PBX3 may be involved in the occurrence and development of glioma, and has potential reference value for the early diagnosis and prediction of prognosis of glioma.

SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/β-Catenin and JAK-2/STAT-3 Signaling Pathways.

Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/β-catenin (wingless-int1/β-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of β-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/β-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients.

Characterization of the m6A/m1A/m5C/m7G-related regulators on the prognosis and immune microenvironment of glioma by integrated analysis of scRNA-seq and bulk RNA-seq data.

Proliferation, metabolism, tumor occurrence and development in gliomas are greatly influenced by RNA modifications. However, no research has integrated the four RNA methylation regulators of m6A, m1A, m5C and m7G in gliomas to analyze their relationship with glioma prognosis and intratumoral heterogeneity. Based on three in-house single-cell RNA-sequencing (scRNA-seq) data, the glioma heterogeneity and characteristics of m6A/m1A/m5C/m7G-related regulators were elucidated. Based on publicly available bulk RNA-sequencing (RNA-seq) data, a risk-score system for predicting the overall survival (OS) for gliomas was established by three machine learning methods and multivariate Cox regression analysis, and validated in an independent cohort. Seven cell types were identified in gliomas by three scRNA-seq data, and 22 m6A/m1A/m5C/m7G-related regulators among the marker genes of different cell subtypes were discovered. Three m6A/m1A/m5C/m7G-related regulators were selected to construct prognostic risk-score model, including EIFA, NSUN6 and TET1. The high-risk patients showed higher immune checkpoint expression, higher tumor microenvironment scores, as well as higher tumor mutation burden and poorer prognosis compared with low-risk patients. Additionally, the area under the curve values of the risk score and nomogram were 0.833 and 0.922 for 3 year survival and 0.759 and 0.885 for 5 year survival for gliomas. EIF3A was significantly highly expressed in glioma tissues in our in-house RNA-sequencing data (p < 0.05). These findings may contribute to further understanding of the role of m6A/m1A/m5C/m7G-related regulators in gliomas, and provide novel and reliable biomarkers for gliomas prognosis and treatment.

EZH2 Inhibition Sensitizes IDH1R132H-Mutant Gliomas to Histone Deacetylase Inhibitor.

Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

DTX2 promotes glioma development via regulation of HLTF

BackgroundHuman Deltex 2 (DTX2) is a ubiquitin E3 ligase that functions as an oncogene and has been shown to participate in many human cancers. However, the role of DTX2 in glioma progression has remained obscure. In this study, we explore the mechanism underlying the function of DTX2 in glioma progression.MethodsThe associations between DTX2 expression and clinical characteristics of glioma were determined by bioinformatic analysis of data from The Cancer Genome Atlas and Human Protein Atlas. The expression of DTX2 in glioma tissues was detected using immunohistochemistry and western blotting. Lentivirus-mediated gene knockdown and overexpression were used to determine the effects of DTX2 and helicase-like transcription element (HLTF) on glioma cell proliferation and migration with CCK-8, cell colony formation, transwell, and wound healing assays; flow cytometry in vitro; and animal models in vivo. The interaction of the DTX2 and HLTF proteins was verified by immunoprecipitation assay and confocal microscopy.ResultsDTX2 was highly expressed in glioma samples, and this was correlated with worse overall survival. Silencing of DTX2 suppressed glioma cell viability, colony formation, and migration and induced cell apoptosis. In vitro ubiquitination assays confirmed that DTX2 could downregulate HLTF protein levels by increasing ubiquitination of the HLTF protein. We also observed that HLTF inhibited proliferation and migration of glioma cells. Subcutaneous xenografts with DTX2-overexpressing U87 cells showed significantly increased tumor volumes and weights.ConclusionsWe have identified DTX2/HLTF as a new axis in the development of glioma that could serve as a prognostic or therapeutic marker.Graphical abstract