Glioma Pathogenesis Research Articles

Comprehensive Analysis of Sterol O-Acyltransferase 1 as a Prognostic Biomarker and Its Association With Immune Infiltration in Glioma.

Metabolic reprogramming is a hallmark of glioma, and sterol O-acyltransferase 1 (SOAT1) is an essential target for metabolic therapy. However, the prognostic value of SOAT1 and its association with immune infiltration has not been fully elucidated. Using RNA-seq and clinical data of glioma patients from The Cancer Genome Atlas (TCGA), SOAT1 was found to be correlated with poor prognosis in glioma and the advanced malignancy of clinicopathological characteristics. Next, the correlation between SOAT1 expression and tumor-infiltrating immune cells was performed using the single-sample GSEA algorithm, gene expression profiling interactive analysis (GEPIA), and tumor immune estimation resource version 2 (TIMER2.0); it was found that SOAT1 expression was positively correlated with multiple tumor-infiltrating immune cells. To further verify these results, immunofluorescence was conducted on paraffin-embedded glioma specimens, and a positive trend of the correlation between SOAT1 expression and Treg infiltration was observed in this cohort. Finally, differentially expressed gene analysis, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to explore the biological processes and signaling pathways that SOAT1 may be involved in during glioma pathogenesis. A protein-protein interaction network was established, and co-expression analysis was conducted to investigate the regulatory mechanism of SOAT1 in glioma. To the best of our knowledge, this is the first comprehensive study reporting that SOAT1 may serve as a novel prognostic biomarker associated with immune infiltrates, providing a novel perspective for glioma metabolic therapy.

The immunogenetics of viral antigen response is associated with subtype-specific glioma risk and survival

Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study, we leveraged genetic predictors of antibody response to 12 viral antigens to investigate the relationship with glioma risk and survival. Genetic reactivity scores (GRSs) for each antigen were derived from genome-wide-significant (p<5×10-8) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution by using data from 3,418 glioma-affected individuals subtyped by somatic mutations and 8,156 controls. Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were associated with glioma risk and survival (Bonferroni-corrected p<0.01). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild-type gliomas (ORZEBRA= 0.91, p= 0.0099/ORMCV= 1.11, p= 0.0054). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR= 1.09, p= 0.040) and improved survival (HR= 0.86, p= 0.010). HLA-DQA1∗03:01 was significantly associated with decreased risk of glioma overall (OR= 0.85, p= 3.96×10-4) after multiple testing adjustment. This systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may inform applications of antiviral-based therapies in glioma treatment.

The Profiles of Tet-Mediated DNA Hydroxymethylation in Human Gliomas.

Gliomas are the most common primary malignant intracranial brain tumors. Their proliferative and invasive behavior is controlled by various epigenetic mechanisms. 5-hydroxymethylcytosine (5-hmC) is one of the epigenetic DNA modifications that employs ten-eleven translocation (TET) enzymes to its oxidation. Previous studies demonstrated altered expression of 5-hmC across gliomagenesis. However, its contribution to the initiation and progression of human gliomas still remains unknown. To characterize the expression profiles of 5-hmC and TET in human glioma samples we used the EpiJET 5-hmC and 5-mC Analysis Kit, quantitative real-time PCR, and Western blot analysis. A continuous decline of 5-hmC levels was observed in solid tissue across glioma grades. However, in glioblastoma (GBM), we documented uncommon heterogeneity in 5-hmC expression. Further analysis showed that the levels of TET proteins, but not their transcripts, may influence the 5-hmC abundance in GBM. Early tumor-related biomarkers may also be provided by the study of aberrant DNA hydroxymethylation in the blood of glioma patients. Therefore, we explored the patterns of TET transcripts in plasma samples and we found that their profiles were variously regulated, with significant value for TET2. The results of our study confirmed that DNA hydroxymethylation is an important mechanism involved in the pathogenesis of gliomas, with particular reference to glioblastoma. Heterogeneity of 5-hmC and TET proteins expression across GBM may provide novel insight into define subtype-specific patterns of hydroxymethylome, and thus help to interpret the heterogeneous outcomes of patients with the same disease.

Analysis of Isocitrate Dehydrogenase (IDH) expression in astrocytoma patients: cases of South Sulawesi, Indonesia

Background: Astrocytoma is the most common primary intracerebral tumor in adults and causes high morbidity and mortality. Most patients with astrocytomas, especially diffuse gliomas, have a poor prognosis. Recent genetic and epigenetic studies have shown that mutations in the Isocitrate Dehydrogenase (IDH) gene play an important role in the pathogenesis and prognosis of gliomas, thus facilitating IDH1 mutations in the population to become an important marker, not only to assist in the diagnosis and prognostic factors of these gliomas but also to develop therapeutic targets as currently available. This study aims to see differences in the expression of the IDH in each astrocytoma classification. Methods: A cross-sectional analytic study was conducted at the Anatomical Pathology Laboratory, Faculty of Medicine, Universitas Hasanuddin, from October 2020 to August 2021. The research sample came from 65 paraffin block preparations for primary brain tumors with the diagnosis of Diffuse Astrocytoma (DA), Anaplastic Astrocytoma (AA) and Glioblastoma (GB). The immunohistochemical staining was performed using the monoclonal antibody IDH1-R132H. The microscopic assessment was carried out using a light microscope. Data were analyzed using SPSS version 20 for Windows. Results: There was a significant relationship between the expression of IDH1-R132H in each astrocytoma classification (p=0.008). The prevalence of astrocytoma with negative IDH1-R132H expression (IDH-wildtype) is lower by 21 samples (32.3%) compared to astrocytoma with positive IDH1-R132H expression (IDH-mutant), which is 44 samples (67.7%). Conclusion: There are significant differences in the expression of IDH1-R132H in Diffuse Astrocytoma, Anaplastic Astrocytoma and Glioblastoma, where the proportion of IDH-mutant status is higher than IDH-wildtype and IDH1 mutation status has a significant relationship with tumor grade.

A tumor suppressor role for EZH2 in diffuse midline glioma pathogenesis

Pediatric high-grade gliomas, specifically diffuse midline gliomas, account for only 20% of clinical cases but are 100% fatal. A majority of the DMG cases are characterized by the signature K27M mutation in histone H3. The H3K27M mutation opposes the function of enhancer of zeste homolog 2 (EZH2), the methyltransferase enzyme of the polycomb repressor complex 2. However, the role of EZH2 in DMG pathogenesis is unclear. In this study, we demonstrate a tumor suppressor function for EZH2 using Ezh2 loss- and gain-of-function studies in H3WT DMG mouse models. Genetic ablation of Ezh2 increased cell proliferation and tumor grade while expression of an Ezh2 gain-of-function mutation significantly reduced tumor incidence and increased tumor latency. Transcriptomic analysis revealed that Ezh2 deletion upregulates an inflammatory response with upregulation of immunoproteasome genes such as Psmb8, Psmb9, and Psmb10. Ezh2 gain-of-function resulted in enrichment of the oxidative phosphorylation/mitochondrial metabolic pathway namely the isocitrate dehydrogenase Idh1/2/3 genes. Pharmacological inhibition of EZH2 augmented neural progenitor cell proliferation, supporting the tumor suppressive role of EZH2. In vivo 7-day treatment of H3K27M DMG tumor bearing mice with an EZH2 inhibitor, Tazemetostat, did not alter proliferation or significantly impact survival. Together our results suggest that EZH2 has a tumor suppressor function in DMG and warrants caution in clinical translation of EZH2 inhibitors to treat patients with DMG.

The Pivotal Immunoregulatory Functions of Microglia and Macrophages in Glioma Pathogenesis and Therapy.

Gliomas are mixed solid tumors composed of both neoplastic and nonneoplastic cells. In glioma microenvironment, the most common nonneoplastic and infiltrating cells are macrophages and microglia. Microglia are the exact phagocytes of the central nervous system, whereas macrophages are myeloid immune cells that are depicted with ardent phagocytosis. Microglia are heterogeneously located in almost all nonoverlapping sections of the brain as well as the spinal cord, while macrophages are derived from circulating monocytes. Microglia and macrophages utilize a variety of receptors for the detection of molecules, particles, and cells that they engulf. Both microglia and peripheral macrophages interact directly with vessels both in the periphery of and within the tumor. In glioma milieu, normal human astrocytes, glioma cells, and microglia all exhibited the ability of phagocytosing glioma cells and precisely apoptotic tumor cells. Also, microglia and macrophages are robustly triggered by the glioma via the expression of chemoattractants such as monocyte chemoattractant protein, stromal-derived factor-1, and macrophage-colony stimulating factor. Glioma-associated microglia and/or macrophages positively correlated with glioma invasiveness, immunosuppression, and patients' poor outcome, making these cells a suitable target for immunotherapeutic schemes.

MiR-16 Inhibits Extracellular Signal-Regulated Kinases (ERK) Mitogen-Activated Protein Kinases (MAPK) Signaling to Affect Epithelial-Mesenchymal Transition (EMT) and Invasion of Glioma Cells

Abnormal MEK1 expression is associated with tumor cell EMT, invasion and metastasis. Decreased miR-16 level is associated with glioma. Bioinformatics analysis showed a relationship between miR-16 and MEK1. This study assessed whether miR-16 regulates MEK1 expression and affects glioma cell EMT and invasion. The tumor tissues and adjacent glioma tissues were collected to measure miR-16 and MEK1 mRNA. The dual luciferase assay validated the relation of miR-16 with MEK1. U251 cells were cultured and assigned into NC group and mimic group, followed by analysis of cell biological behaviors, and MEK1, p-ERK1/2, E-cadherin, N-Cadherin expression. Compared with adjacent tissues, miR-16 expression was significantly decreased and MEK1 was elevated in glioma tissues. Compared with HEB, miR-16 in glioma U251 and SHG44 cells was decreased and MEK1 was increased. Dual luciferase reporter gene experiments confirmed the relation of miR-16 with MEK1. Transfection of miR-16 mimic significantly down-regulated MEK1, p-ERK1/2 and N-cadherin in U251 cells, upregulated E-cadherin, inhibited cell proliferation, promoted apoptosis, and attenuated EMT and invasion of glioma cells. In conclusion, decreased miR-16 expression and increased MEK1 expression is related to glioma pathogenesis. Overexpression of miR-16 can inhibit MEK1 expression, ERK/MAPK signaling, glioma cell proliferation, promote apoptosis, and attenuate EMT and invasion.

LncRNA HOTAIR sponges miR-301a-3p to promote glioblastoma proliferation and invasion through upregulating FOSL1

Glioblastoma, one of the most fatal brain tumors, is associated with a dismal prognosis and an extremely short overall survival. We previously reported that the overexpressed transient receptor potential channel TRPM7 is an essential glioblastoma regulator. Accumulating evidence suggests that long noncoding RNAs (lncRNAs) play an important role in glioma's initiation and progression. However, the function of lncRNA, HOX transcript antisense intergenic RNA (HOTAIR) mediated by TRPM7 in glioma remains unclear. In this study, HOTAIR expression was found to be positively regulated by TRPM7, significantly upregulated in glioma tissues, and is a poor prognosis factor for glioma patients. Moreover, reduced HOTAIR expression impeded the proliferation and invasion of glioma cells. Mechanistically, HOTAIR directly interacted with miR-301a-3p, and downregulation of miR-301a-3p efficiently reversed FOSL1 suppression induced by siRNA HOTAIR, which implied that HOTAIR positively regulated FOSL1 level through sponging miR-301a-3p and played an oncogenic role in glioma progression. In contrast to HOTAIR's role, miR-301a-3p alone served as a tumor suppressor to decrease glioma cell viability and migration/invasion. In agreement with HOTAIR's role, FOSL1 functioned as a tumorigenic gene in glioma pathogenesis, which was highly expressed in glioma tissues, and was shown to be an unfavorable prognostic factor for glioma patients. Mechanically, FOSL1 inhibition by siRNA FOSL1 efficiently rescued the oncogenic-like phenotypes caused by the miR-301a-3p inhibitor in glioma pathogenesis. SignificanceOur study elucidated the role of TRPM7-mediated HOTAIR as a miRNA sponge to target downstream FOSL1 oncogene and therefore consequently contribute to gliomagenesis, which shed new light on TRPM7/lncRNA-directed diagnostic and therapeutic approach in glioma.

Genome-Wide Analysis for the Regulation of Gene Alternative Splicing by DNA Methylation Level in Glioma and its Prognostic Implications

Glioma is a primary high malignant intracranial tumor with poorly understood molecular mechanisms. Previous studies found that both DNA methylation modification and gene alternative splicing (AS) play a key role in tumorigenesis of glioma, and there is an obvious regulatory relationship between them. However, to date, no comprehensive study has been performed to analyze the influence of DNA methylation level on gene AS in glioma on a genome-wide scale. Here, we performed this study by integrating DNA methylation, gene expression, AS, disease risk methylation at position, and clinical data from 537 low-grade glioma (LGG) and glioblastoma (GBM) individuals. We first conducted a differential analysis of AS events and DNA methylation positions between LGG and GBM subjects, respectively. Then, we evaluated the influence of differential methylation positions on differential AS events. Further, Fisher’s exact test was used to verify our findings and identify potential key genes in glioma. Finally, we performed a series of analyses to investigate influence of these genes on the clinical prognosis of glioma. In total, we identified 130 glioma-related genes whose AS significantly affected by DNA methylation level. Eleven of them play an important role in glioma prognosis. In short, these results will help to better understand the pathogenesis of glioma.

MicroRNA-3200-3p targeting CAMK2A modulates the proliferation and metastasis of glioma in vitro

ABSTRACT MicroRNA (miRNA) is strongly interrelated with the pathogenesis of glioma. However, its potential biological effect and underlying mechanism of miR-3200-3p in human glioma remain elusive. In the current study, we checked the level of miR-3200-3p in different glioma cells. Then, its biological functions on glioma cell proliferation metastasis was investigated using the miR-3200-3p mimic and inhibitor. The direct target of miR-3200-3p was tested in these cells. Results demonstrated that miR-3200-3p is remarkably downregulated in human glioma cells. The relative level of miR-3200-3p is strongly associated with biological features, including proliferation, colony formation, and metastasis. Additionally, Ca2+/calmodulin dependent kinase 2a (CAMK2A) might be the direct target gene of miR-3200-3p, and CAMK2A overexpression reversed the anticancer roles of miR-3200-3p on glioma cellular function. Importantly, these results further showed that miR-3200-3p downregulated the proliferation and metastasis by suppressing the expression of CAMK2A, thus regulating the Ras/Raf/MEK/ERK pathway. This study provided provided insights into the biological role of miR-3200-3p, which might function as a potential biomarker in glioma therapy.

CRISPR screening of E3 ubiquitin ligases reveals Ring Finger Protein 185 as a novel tumor suppressor in glioblastoma repressed by promoter hypermethylation and miR-587

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor. E3 ligases play important functions in glioma pathogenesis. CRISPR system offers a powerful platform for genome manipulation, while the screen of E3 ligases in GBM still remains to be explored. Here, we first constructed an E3 ligase small guide RNA (sgRNAs) library for glioma cells growth screening. After four passages, 299 significantly enriched or lost genes (SELGs) were compared with the initial state. Then the clinical significance of SELGs were validated and analyzed with TCGA glioblastoma and CGGA datasets. As RNF185 showed lost signal, decreased expression and favorable prognostic significance, we chose RNF185 for functional analysis. In vitro overexpressed cellular phenotype showed that RNF185 was a tumor suppressor in two glioma cell lines. Finally, the molecular mechanism of decreased RNF185 expression was investigated and increased miR-587 expression and DNA hypermethylation was evaluated. This study would provide a link between the molecular basis and glioblastoma pathogenesis, and a novel perspective for glioblastoma treatment.

Natural products in suppressing glioma progression: A focus on the role of microRNAs.

Glioma is one of the most common malignancies of the central nervous system. Due to inadequate response to the current treatments available, glioma has been at the center of recent cancer studies searching for novel treatment strategies. This has prompted an intensive search using linkage studies and preliminary evidence to gain efficient insight into the mechanisms involved in the alleviation of the pathogenesis of glioma mediated by miRNAs, a group of noncoding RNAs that affect gene expression posttranscriptionally. Dysregulated expression of miRNAs can exacerbate the malignant features of tumor cells in glioma and other cancers. Natural products can exert anticancer effects on glioma cells by stimulating the expression levels of tumor suppressor miRNAs and repressing the expression levels of oncogenic miRNAs. In this review, we aimed to collect and analyze the literature addressing the roles of natural products in the treatment of glioma, with an emphasis on their involvement in the regulation of miRNAs.

Identification of Ferroptosis-Related Biomarkers for Prognosis and Immunotherapy in Patients With Glioma.

Ferroptosis is a novel type of iron- and ROS-dependent cell death and is involved in various diseases. LncRNAs are involved and play important roles in the occurrence and development of several cancers. However, researches about the role of ferroptosis-related lncRNAs in glioma are relatively rare. Here, we identified nine ferroptosis-related lncRNAs and then constructed a prognostic model by the LASSO and Cox analysis. The model could predict overall survival with high sensitivity and specificity according to ROC curves. In addition, the cell cycle, p53 signaling, apoptosis, and oxidative phosphorylation pathways were obviously enriched in the pathogenesis of glioma by gene set enrichment analysis. A nomogram was constructed by integrating several independent prognostic clinicopathological features, and it could provide a valuable predictive tool for overall survival. Furthermore, a strong correlation between these nine lncRNAs and immunotherapy was found. Glioma patients in the high-risk group had higher TMB using somatic mutation data, different immune infiltration, and higher expression of immune checkpoints, indicating these patients might benefit from immune checkpoint inhibitor therapy. In summary, these nine ferroptosis-related lncRNAs were promising biomarkers for predicting overall survival and guiding immunotherapy or future immune checkpoint inhibitor development for glioma patients.

NOX2-Induced High Glycolytic Activity Contributes to the Gain of COL5A1-Mediated Mesenchymal Phenotype in GBM.

Simple SummaryGlioblastoma multiforme (GBM) is the most aggressive type of glioma and exhibits extensive heterogeneity and poor prognosis with a high recurrence rate. Among the genetic alterations in GBM with different phenotypic states, a mesenchymal subtype has been associated with a worse outcome in patients with GBM. The mechanisms for the gain of the mesenchymal subtype in GBM remain unclear. Our aim was to investigate whether NOX2-induced high glycolytic activity could contribute to the gain of the mesenchymal phenotype in GBM. We revealed that NOX2-induced high glycolytic activity can induce the gain of the COL5A1-mediated mesenchymal phenotype in GBM. Our findings will provide the molecular mechanism by which NOX2 contributes to the gain of mesenchymal phenotype in GBM.The alteration of the cellular metabolism is a hallmark of glioma. The high glycolytic phenotype is a critical factor in the pathogenesis of high-grade glioma, including glioblastoma multiforme (GBM). GBM has been stratified into three subtypes as the proneural, mesenchymal, and classical subtypes. High glycolytic activity was found in mesenchymal GBM relative to proneural GBM. NADPH oxidase 2 (NOX2) has been linked to cellular metabolism and epithelial-mesenchymal transition (EMT) in tumors. The role of NOX2 in the regulation of the high glycolytic phenotype and the gain of the mesenchymal subtype in glioma remain unclear. Here, our results show that the levels of NOX2 were elevated in patients with GBM. NOX2 induces hexokinase 2 (HK2)-dependent high glycolytic activity in U87MG glioma cells. High levels of NOX2 are correlated with high levels of HK2 and glucose uptake in patients with GBM relative to benign glioma. Moreover, NOX2 increases the expression of mesenchymal-subtype-related genes, including COL5A1 and FN1 in U87MG glioma cells. High levels of NOX2 are correlated with high levels of COL5A1 and the accumulation of extracellular matrix (ECM) in patients with GBM relative to benign glioma. Furthermore, high levels of HK2 are correlated with high levels of COL5A1 in patients with GBM relative to benign glioma. Our results suggest that NOX2-induced high glycolytic activity contributes to the gain of the COL5A1-mediated mesenchymal phenotype in GBM.

Current Understanding of Exosomal MicroRNAs in Glioma Immune Regulation and Therapeutic Responses.

Exosomes, the small extracellular vesicles, are released by multiple cell types, including tumor cells, and represent a novel avenue for intercellular communication via transferring diverse biomolecules. Recently, microRNAs (miRNAs) were demonstrated to be enclosed in exosomes and therefore was protected from degradation. Such exosomal miRNAs can be transmitted to recipient cells where they could regulate multiple cancer-associated biological processes. Accumulative evidence suggests that exosomal miRNAs serve essential roles in modifying the glioma immune microenvironment and potentially affecting the malignant behaviors and therapeutic responses. As exosomal miRNAs are detectable in almost all kinds of biofluids and correlated with clinicopathological characteristics of glioma, they might be served as promising biomarkers for gliomas. We reviewed the novel findings regarding the biological functions of exosomal miRNAs during glioma pathogenesis and immune regulation. Furthermore, we elaborated on their potential clinical applications as biomarkers in glioma diagnosis, prognosis and treatment response prediction. Finally, we summarized the accessible databases that can be employed for exosome-associated miRNAs identification and functional exploration of cancers, including glioma.

Effects of ESCO2 or its methylation on the prognosis, clinical characteristics, immune microenvironment, and pathogenesis of low-grade glioma

The establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) has an important regulatory effect on cell proliferation and division, which is closely related to the malignant process of glioma cells. Therefore, this study attempts to provide a target for biologically targeted therapy for low-grade glioma (LGG) by demonstrating the regulatory effect of ESCO2 during the pathological process of LGG. First, the 1064 samples of LGG transcriptomic data and corresponding clinicopathological information obtained from various databases were included in the study. Second, the chi-squared test showed that the expression of ESCO2 was associated with the malignant characteristics of LGG (recurrence and grade), and Kaplan Meier and multivariate analysis suggested that ESCO2 was an independent risk factor, resulting in a significant reduction in the overall duration of survival of patients. Third, co-expression analysis showed that the level of mRNA expression of ESCO2 was negatively regulated by multiple methylation sites (cg04108328, cg12564175, and cg26534677), and the hypermethylation status of cg12564175 could prolong the overall survival of patients. Fourth, the Tumor Immune Estimation Resource (TIMER) database shows that ESCO2 can have a positive regulatory relationship with six different immune cells, such as CD8 + T cells and macrophages, and a positive expression relationship with PD-1 and PD-L1. Finally, Gene Set Enrichment Analysis (GSEA) showed that ESCO2 may play a carcinogenic role by affecting cell replication and DNA repair. In summary, this study confirmed the carcinogenic effect of ESCO2 on LGG for the first time. It is speculated that both the mRNA of ESCO2 and its methylation site (cg12564175) can be useful biological targets for molecular targeted therapy of LGG.

Exosomal circRNA_104948 Enhances the Progression of Glioma by Regulating miR-29b-3p and DNMT3B/MTSS1 Signaling.

Glioma is a common type of malignancy in the central nervous system. The pathogenesis of glioma is complex and the underlying mechanisms remain largely unknown. In our study, exosomes were exacted from patient samples, and the isolated exosomes were confirmed by transmission electron microscope. The expression of circRNA_104948, miR-29b-3p and DNMT3B were determined using RT-qPCR. Proliferative activity of cell was examined using CCK-8 assay. Cell apoptotic rate was evaluated by flow cytometry. The expression levels of proliferation or apop-tosis markers were determined using western blotting. Our data suggested that circRNA_104948 was upregulated in plasma exosomes/tissue samples of glioma patients and glioma cell lines. Furthermore, cell proliferation was enhanced and apoptosis was suppressed in normal astrocytes treated with exosomal circRNA_104948, and the effects were reversed by sh-circRNA_104948. In addition, miR-29b-3p is a novel target of circRNA_104948, and DNMT3B is a putative downstream molecule of miR-29b-3p. circRNA_104948 could regulate the proliferation/apoptosis of astrocytes through miR-29b-3p/DNMT3B/MTSS1 signaling, and the biological behavior changes induced by glioma-Exo were reversed by miR-29b-3p mimics; upregulated cell growth caused by miR-29b-3p inhibitors was abrogated by the knockdown of DNMT3B; the effects induced by miR-29b-3p mimics were abolished by the overexpression of DNMT3B. Our findings revealed the important roles of circRNA_104948 on the development of glioma, and circRNA_104948/miR-29b-3p/MTSS1/DNMT3B pathway may be a potential candidate for the target therapy of glioma patients.

TM4SF1 promotes glioma malignancy through multiple mechanisms.

Transmembrane-4 L Six Family member 1 (TM4SF1) belongs to a family of integral membrane proteins implicated in cell growth and tumor progression. Glioma is the most common and aggressive malignant brain tumor in adults. In this study, we showed that TM4SF1 was highly expressed in glioma tumor tissues and cell lines. The expression levels of TM4SF1 were negatively correlated with patients' survival rates. Silencing TM4SF1 by RNA interference inhibited the proliferation, migration, and invasion of glioma cells. Moreover, TM4SF1 silencing induced glioma cell cycle arrest and early apoptosis. In contrast, overexpression of TM4SF1 in glioma cells exhibited the opposite effects. Mechanistically, we found that loss of TM4SF1 reduced phospho-ATK, Cyclin D1, Bcl-2, and MMP-9 levels in glioma cells. Taken together, these findings provide novel insights into glioma pathogenesis and suggest that TM4SF1 may represent a novel target for glioma intervention.

XAF1 directs glioma response to temozolomide through apoptotic transition of autophagy by activation of ATM-AMPK signaling.

BackgroundX-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a tumor suppressor that is commonly inactivated in multiple human cancers. However, its role in the pathogenesis and therapeutic response of glioma is poorly characterized.MethodsXAF1 activation by temozolomide (TMZ) and its effect on TMZ cytotoxicity were defined using luciferase reporter, flow cytometry, and immunofluorescence assays. Signaling mechanism was analyzed using genetic and pharmacologic experiments. In vivo studies were performed in mice to validate the role of XAF1 in TMZ therapy.ResultsEpigenetic alteration of XAF1 is frequent in cell lines and primary tumors and contributes to cancer cell growth. XAF1 transcription is activated by TMZ via JNK–IRF-1 signaling to promote apoptosis while it is impaired by promoter hypermethylation. In tumor cells expressing high O6-methylguanine-DNA methyltransferase (MGMT), XAF1 response to TMZ is debilitated. XAF1 facilitates TMZ-mediated autophagic flux to direct an apoptotic transition of protective autophagy. Mechanistically, XAF1 is translocated into the mitochondria to stimulate reactive oxygen species (ROS) production and ataxia telangiectasia mutated (ATM)–AMP-activated protein kinase (AMPK) signaling. A mutant XAF1 lacking the zinc finger 6 domain fails to localize in the mitochondria and activate ROS–ATM–AMPK signaling and autophagy-mediated apoptosis. XAF1-restored xenograft tumors display a reduced growth rate and enhanced therapeutic response to TMZ, which is accompanied with activation of ATM–AMPK signaling. XAF1 expression is associated with overall survival of TMZ treatment patients, particularly with low MGMT cancer.ConclusionsThis study uncovers an important role for the XAF1–ATM–AMPK axis as a linchpin to govern glioma response to TMZ therapy.

Identification of proteins of laminated layer of Echinococcus granulosus: Interface among host and parasite

Cystic echinococcosis is one of the major echinococcosis which is caused by the larval form of tape worm Echinococcus granulosus. The chronicity of the parasitic infection is related to the strategies adopted by parasite to escape the host immuneresponse. Several studies were performed to clarify the host-Echinococcus granulosus interaction allowing the adaptation of the metacestode to the host. Many proteomics analyses allowed the identification of proteins in hydatid fluid, protoscoleces adult worm and hydatid walls. Our study is focused on the identification of proteins associated to the laminated layer which constitutes the interface between metacestode and the host immune response. In this context, protein extracts obtained were separated by SDS-PAGE and analyzed by nano-liquid chromatography-coupled tandem mass spectrometry. Our results revealed the presence of host proteins. Most of them were sera proteins and would be involved in the immune response indicating their involvement in the local inflammatory response and others involved in transport. Interestingly, our results also identified a few parasitic proteins such as glioma pathogenesis protein 1, paramyosin, and myoferlin. Globally, our study indicated the presence of proteins that might be involved in host-parasite interaction and pointed some of them as potential drug and vaccine targets.