Pathogenesis Of Glioblastoma Multiforme Research Articles

Development of a hydrogel-based three-dimensional (3D) glioblastoma cell lines culture as a model system for CD73 inhibitor response study

BackgroundDespite the development of various therapeutic approaches over the past decades, the treatment of glioblastoma multiforme (GBM) remains a major challenge. The extracellular adenosine-generating enzyme, CD73, is involved in the pathogenesis and progression of GBM, and targeting CD73 may represent a novel approach to treat this cancer. In this study, three-dimensional culture systems based on three hydrogel compositions were characterized and an optimal type was selected to simulate the GBM microenvironment. In addition, the effect of a CD73 inhibitor on GBM cell aggregates and spheroids was investigated as a potential therapeutic approach for this disease.MethodsRheology measurements, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and cell proliferation assays were performed to analyze the synthesized hydrogel and select an optimal formulation. The viability of tumor cells in the optimal hydrogel was examined histologically and by confocal microscopy. In addition, the sensitivity of the tumor cells to the CD73 inhibitor was investigated using a cell proliferation assay and real-time PCR.ResultsThe data showed that the hydrogel containing 5 wt% gelatin and 5 wt% sodium alginate had better rheological properties and higher cell viability. Therefore, it could provide a more suitable environment for GBM cells and better mimic the natural microenvironment. GBM cells treated with CD73 inhibitors significantly decreased the proliferation rate and expression of VEGF and HIF1-α in the optimal hydrogel.ConclusionOur current research demonstrates the great potential of CD73 inhibitor for clinical translation of cancer studies by analyzing the behavior and function of 3D tumor cells, and thus for more effective treatment protocols for GBM.

Glioblastoma Multiforme miRNA based Comprehensive Study to Validate Phytochemicals for Effective Treatment against Deadly Tumour through In Silico Evaluation.

Glioblastoma Multiforme (GBM) is a prevalent and deadly type of primary astrocytoma, constituting over 60% of adult brain tumors, and has a poor prognosis, with a high relapse rate within 7 months of diagnosis. Despite surgical, radiotherapy, and chemotherapy treatments, GBM remains challenging due to resistance. MicroRNA (miRNAs) control gene expression at transcriptional and post-transcriptional levels by targeting their messenger RNA (mRNA), and also contribute to the development of various neoplasms, including GBM. The present study focuses on exploring the miRNAs-based pathogenesis of GBM and evaluating most potential plant-based therapeutic agents with in silico analysis. Gene chips were retrieved from the Gene Expression Omnibus (GEO) database, followed by the Robust- Rank- Aggereg algorithm to determine the Differentially Expressed miRNAs (DEMs). The predicted targets were intersected with the GBM-associated genes, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the overlapping genes was performed. At the same time, five phytochemicals were selected for the Connectivity map (CMap), and the most efficient ones were those that had undergone molecular docking analysis to obtain the potential therapeutic agents. The hsa-miR-10b, hsa-miR-21, and hsa-miR-15b were obtained, and eight genes were found to be associated with glioma pathways; VSIG4, PROCR, PLAT, and ITGB2 were upregulated while, CAMK2B, PDE1A, GABRA1, and KCNJ6 were downregulated. The drugs Resveratrol and Quercetin were identified as the most prominent drugs. These miRNAs-based drugs can be used as a curative agent for the treatment of GBM. However, in vivo, experimental data, and clinical trials are necessary to provide an alternative to conventional GBM cancer chemotherapy.

Artificial intelligence and omics in malignant gliomas.

Glioblastoma multiforme (GBM) is one of the most common and aggressive type of malignant glioma with an average survival time of 12-18 mo. Despite the utilization of extensive surgical resections using cutting-edge neuroimaging, and advanced chemotherapy and radiotherapy, the prognosis remains unfavorable. The heterogeneity of GBM and the presence of the blood-brain barrier further complicate the therapeutic process. It is crucial to adopt a multifaceted approach in GBM research to understand its biology and advance toward effective treatments. In particular, omics research, which primarily includes genomics, transcriptomics, proteomics, and epigenomics, helps us understand how GBM develops, finds biomarkers, and discovers new therapeutic targets. The availability of large-scale multiomics data requires the development of computational models to infer valuable biological insights for the implementation of precision medicine. Artificial intelligence (AI) refers to a host of computational algorithms that is becoming a major tool capable of integrating large omics databases. Although the application of AI tools in GBM-omics is currently in its early stages, a thorough exploration of AI utilization to uncover different aspects of GBM (subtype classification, prognosis, and survival) would have a significant impact on both researchers and clinicians. Here, we aim to review and provide database resources of different AI-based techniques that have been used to study GBM pathogenesis using multiomics data over the past decade. We summarize different types of GBM-related omics resources that can be used to develop AI models. Furthermore, we explore various AI tools that have been developed using either individual or integrated multiomics data, highlighting their applications and limitations in the context of advancing GBM research and treatment.

Exploring the potentials of S4, a selective androgen receptor modulator, in glioblastoma multiforme therapy

Glioblastoma multiforme (GBM) ranks among the prevalent neoplastic diseases globally, presenting challenges in therapeutic management. Traditional modalities have yielded suboptimal response rates due to its intrinsic pathological resistance. This underscores the imperative for identifying novel molecular targets to enhance therapeutic efficacy. Literature indicates a notable correlation between androgen receptor (AR) signaling and GBM pathogenesis. To mitigate the adverse effects associated with androgenic modulation of AR, scientists have pivoted towards the synthesis of non-steroidal anabolic agents, selective androgen receptor modulators (SARMs). Among these, S4, used as a supplement by the bodybuilders to efficiently grow muscle mass with favourable oral bioavailability has emerged as a candidate of interest. This investigation substantiates the anti-oncogenic potential of S4 in temozolomide-responsive and -resistant GBM cells through cellular and molecular evaluations. We observed restriction in GBM cell growth, and motility, coupled with an induction of apoptosis, reactive oxygen species (ROS) generation, and cellular senescence. S4 exposure precipitated the upregulation of genes associated with apoptosis, cell-cycle arrest, DNA damage response, and senescence, while concurrently downregulating those involved in cellular proliferation. Future research endeavours are warranted to delineate the mechanisms underpinning S4's actions, assess its antineoplastic effects in-vivo, and its ability to penetrate the blood-brain barrier.

Dissecting causal relationships between gut microbiota, blood metabolites, and glioblastoma multiforme: a two-sample Mendelian randomization study.

Given the increasing interest in the role of gut microbiota in glioblastoma multiforme (GBM), our objective was to examine the potential causal relationship between gut microbiota and GBM, as well as the mediating effects of specific metabolites. A bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the associations between 196 microbial taxa and GBM. A two-step MR technique was used to identify significant mediators in this relationship. Subsequently, a mediation analysis was performed to explore and quantify the mediating effects of specific metabolites on the causal relationship between gut microbiota and GBM. Five taxa showed significant associations with GBM. Among them, family Victivallaceae [odds ratio (OR): 1.95; 95% confidence interval (CI): 1.21, 3.13; p = 0.005] and genus Lactococcus (OR: 1.81; 95% CI: 1.04, 3.15; p = 0.036) were positively correlated with the risk of GBM, while phylum Cyanobacteria had a protective effect against GBM (OR: 0.45; 95% CI: 0.22, 0.89; p = 0.021). The mediation analysis revealed that the connections among family Victivallaceae, genus Lactococcus, phylum Cyanobacteria and GBM were mediated by Methyl-4-hydroxybenzoate sulfate, phosphoethanolamine and dehydroepiandrosterone sulfate. Each of these accounted for 7.27, 7.98, and 8.65%, respectively. Our study provides evidence supporting a potential causal association between certain gut microbiota taxa and GBM. The study highlights the central role of gut microbiota in GBM pathogenesis and their interactions with vital serum metabolites. This paves the way for potential novel therapeutic interventions in GBM management.

Speeding up Glioblastoma Cancer Research: Highlighting the Zebrafish Xenograft Model

Glioblastoma multiforme (GBM) is a very aggressive and lethal primary brain cancer in adults. The multifaceted nature of GBM pathogenesis, rising from complex interactions between cells and the tumor microenvironment (TME), has posed great treatment challenges. Despite significant scientific efforts, the prognosis for GBM remains very poor, even after intensive treatment with surgery, radiation, and chemotherapy. Efficient GBM management still requires the invention of innovative treatment strategies. There is a strong necessity to complete cancer in vitro studies and in vivo studies to properly evaluate the mechanisms of tumor progression within the complex TME. In recent years, the animal models used to study GBM tumors have evolved, achieving highly invasive GBM models able to provide key information on the molecular mechanisms of GBM onset. At present, the most commonly used animal models in GBM research are represented by mammalian models, such as mouse and canine ones. However, the latter present several limitations, such as high cost and time-consuming management, making them inappropriate for large-scale anticancer drug evaluation. In recent years, the zebrafish (Danio rerio) model has emerged as a valuable tool for studying GBM. It has shown great promise in preclinical studies due to numerous advantages, such as its small size, its ability to generate a large cohort of genetically identical offspring, and its rapid development, permitting more time- and cost-effective management and high-throughput drug screening when compared to mammalian models. Moreover, due to its transparent nature in early developmental stages and genetic and anatomical similarities with humans, it allows for translatable brain cancer research and related genetic screening and drug discovery. For this reason, the aim of the present review is to highlight the potential of relevant transgenic and xenograft zebrafish models and to compare them to the traditionally used animal models in GBM research.

Autophagy-related CMTM6 promotes glioblastoma progression by activating Wnt/β-catenin pathway and acts as an onco-immunological biomarker.

Glioblastoma multiforme (GBM) is identified as one of the most prevalent and malignant brain tumors, characterized by poor treatment outcomes and a limited prognosis. CMTM6, a membrane protein, has been found to upregulate the expression of programmed cell death 1 ligand 1 protein (PD-L1) and acts as an immune checkpoint inhibitor by inhibiting the programmed death 1 protein/PD-L1 signaling pathway. Recent research has demonstrated a high expression of CMTM6 in GBM, suggesting its potential role in influencing the pathogenesis and progression of GBM, as well as its association with immune cell infiltration in the tumor microenvironment. However, the underlying mechanism of CMTM6 in GBM requires further investigation. Data from cancer patients in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas cohorts were consolidated for the current study. Through multi-omics analysis, the study systematically examined the expression profile of CMTM6, epigenetic modifications, prognostic significance, biological functions, potential mechanisms of action and alterations in the immune microenvironment. Additionally, the study investigated CMTM6 expression in GBM cell lines and normal cells using reverse transcription PCR and western blot analysis. The impact of CMTM6 on GBM cell proliferation, migration and invasion was evaluated using a combination of cell counting kit-8 assay, clone formation assay, 5-ethynyl-2'-deoxyuridine incorporation assay, wound healing assay and Transwell assay. In order to explore the mechanism of CMTM6, the Wnt/β-catenin signaling pathway and autophagy-related genes were further verified through western blot analysis. CMTM6 is highly expressed in multiple tumors, particularly GBM. CMTM6 has been shown to be a valuable diagnostic and prognostic biomarker by various bioinformatics approaches. Additionally, CMTM6 plays a pivotal role in the pathogenesis of cancer, specifically GBM, by modulating various biological processes such as DNA methyltransferase expression, RNA modification, copy number variation, genomic heterogeneity, tumor stemness and DNA methylation. The findings of the experiment indicate a significant correlation between elevated CMTM6 expression and the proliferation, invasion, migration and autophagy of GBM cells, with potential key roles mediated through the Wnt/β-catenin signaling pathway. Furthermore, CMTM6 is implicated in modulating tumor immune cell infiltration and is closely linked to the expression of various immune checkpoint inhibitors and immune modulators, particularly within the context of GBM. High levels of CMTM6 expression also enhance the responsiveness of GBM patients to radiotherapy and chemotherapy, thereby offering valuable insights for guiding treatment strategies for GBM. Autophagy-related CMTM6 is highly expressed in various types of cancer, especially GBM, and it can regulate GBM progression through the Wnt/β-catenin signaling pathway and is capable of being used as an underlying target for the diagnosis, treatment selection and prognosis of patients with GBM.

The PTPRZ1-MET/STAT3/ISG20 axis in glioma stem-like cells modulates tumor-associated macrophage polarization

Recent studies have revealed that PTPRZ1-MET (ZM) fusion plays a pivotal role in the progression of glioma to glioblastoma multiforme (GBM), thus serving as a biomarker to distinguish between primary GBM and secondary GBM (sGBM). However, the mechanisms through which ZM fusion influences this progression remain to be elucidated. GBMs with ZM showed poorer prognoses and greater infiltration of tumor-associated macrophages (TAMs) than those without ZM. Glioma stem-like cells (GSCs) and TAMs play complex roles in glioma recurrence, glioma progression and therapy resistance. In this study, we analyzed RNA-seq data from sGBM patients' glioma tissues with or without ZM fusion, and found that stemness and macrophage markers were more highly expressed in sGBM patients harboring ZM than in those without ZM fusion. ZM enhanced the self-renewal and proliferation of GSCs, thereby accelerating glioma progression. In addition, ZM-positive GSCs facilitated the infiltration of TAMs and drove their polarization toward an immunosuppressive phenotype, which was primarily accomplished through the extracellular secretion of ISG20. Our research identified the MET–STAT3–ISG20 axis within GSCs, thus demonstrating the critical role of ZM in GBM initiation and progression. Our study demonstrated that, in contrast to ZM-positive differentiated glioma cells, ZM-positive GSCs upregulated ISG20 expression through the MET–STAT3–ISG20 axis. The extracellular secretion of ISG20 recruited and induced M2-like polarization in macrophages, thereby promoting tumor progression. Our results reveal a novel mechanism involved in ZM-positive GBM pathogenesis and identify potential therapeutic targets.

The systematic identification of survival-related alternative splicing events and splicing factors in glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, making it one of the most life-threatening human cancers. Nevertheless, research on the mechanism of action between alternative splicing (AS) and splicing factor (SF) or biomarkers in GBM is limited. AS is a crucial post-transcriptional regulatory mechanism. More than 95% of human genes undergo AS events. AS can diversify the expression patterns of genes, thereby increasing the diversity of proteins and playing a significant role in the occurrence and development of tumors. In this study, we downloaded 599 clinical data and 169 transcriptome analysis data from The Cancer Genome Atlas (TCGA) database. Besides, we collected AS data about GBM from TCGA-SpliceSeq. The overall survival (OS) related AS events in GBM were determined through least absolute shrinkage and selection operator (Lasso) and Cox analysis. Subsequently, the association of these 1825 OS-related AS events with patient survival was validated using the Kaplan-Meier survival analysis, receiver operating characteristic curve, risk curve analysis, and independent prognostic analysis. Finally, we depicted the AS-SF regulatory network, illustrating the interactions between splicing factors and various AS events in GBM. Additionally, we identified three splicing factors (RNU4-1, SEC31B, and CLK1) associated with patient survival. In conclusion, based on AS occurrences, we developed a predictive risk model and constructed an interaction network between GBM-related AS events and SFs, aiming to shed light on the underlying mechanisms of GBM pathogenesis and progression.

Biomolecules to Biomarkers? U87MG Marker Evaluation on the Path towards Glioblastoma Multiforme Pathogenesis.

The heterogeneity of the glioma subtype glioblastoma multiforme (GBM) challenges effective neuropathological treatment. The reliance on in vitro studies and xenografted animal models to simulate human GBM has proven ineffective. Currently, a dearth of knowledge exists regarding the applicability of cell line biomolecules to the realm of GBM pathogenesis. Our study's objectives were to address this preclinical issue and assess prominin-1, ICAM-1, PARTICLE and GAS5 as potential GBM diagnostic targets. The methodologies included haemoxylin and eosin staining, immunofluorescence, in situ hybridization and quantitative PCR. The findings identified that morphology correlates with malignancy in GBM patient pathology. Immunofluorescence confocal microscopy revealed prominin-1 in pseudo-palisades adjacent to necrotic foci in both animal and human GBM. Evidence is presented for an ICAM-1 association with degenerating vasculature. Significantly elevated nuclear PARTICLE expression from in situ hybridization and quantitative PCR reflected its role as a tumor activator. GAS5 identified within necrotic GBM validated this potential prognostic biomolecule with extended survival. Here we present evidence for the stem cell marker prominin-1 and the chemotherapeutic target ICAM-1 in a glioma animal model and GBM pathology sections from patients that elicited alternative responses to adjuvant chemotherapy. This foremost study introduces the long non-coding RNA PARTICLE into the context of human GBM pathogenesis while substantiating the role of GAS5 as a tumor suppressor. The validation of GBM biomarkers from cellular models contributes to the advancement towards superior detection, therapeutic responders and the ultimate attainment of promising prognoses for this currently incurable brain cancer.

The Role of Progranulin (PGRN) in the Pathogenesis of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) represents the most common and aggressive malignant form of brain tumour in adults and is characterized by an extremely poor prognosis with dismal survival rates. Currently, expanding concepts concerning the pathophysiology of GBM are inextricably linked with neuroinflammatory phenomena. On account of this fact, the identification of novel pathomechanisms targeting neuroinflammation seems to be crucial in terms of yielding successful individual therapeutic strategies. In recent years, the pleiotropic growth factor progranulin (PGRN) has attracted significant attention in the neuroscience and oncological community regarding its neuroimmunomodulatory and oncogenic functions. This review of the literature summarizes and updates contemporary knowledge about PGRN, its associated receptors and signalling pathway involvement in GBM pathogenesis, indicating possible cellular and molecular mechanisms with potential diagnostic, prognostic and therapeutic targets in order to yield successful individual therapeutic strategies. After a review of the literature, we found that there are possible PGRN-targeted therapeutic approaches for implementation in GBM treatment algorithms both in preclinical and future clinical studies. Furthermore, PGRN-targeted therapies exerted their highest efficacy in combination with other established chemotherapeutic agents, such as temozolomide. The results of the analysis suggested that the possible implementation of routine determinations of PGRN and its associated receptors in tumour tissue and biofluids could serve as a diagnostic and prognostic biomarker of GBM. Furthermore, promising preclinical applications of PGRN-related findings should be investigated in clinical studies in order to create new diagnostic and therapeutic algorithms for GBM treatment.

HSV1 microRNAs in glioblastoma development: an in silico study

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor. Recent findings highlighted the significance of viral microRNAs (miRs) in regulating post-transcriptional mRNA expression in various human conditions. Although HSV1 encodes viral miRs and affects the central nervous system, no study investigated the roles of HSV1-encoding miRs in GBM development. This study applied in silico approaches to investigate whether HSV1-encoding miRs are involved in GBM development and, if so, how they regulate tumor-suppressive/oncogenes expression in GBM. This study leveraged bioinformatics approaches to identify the potential effect of HSV1 miRs in GBM development. The GSE158284, GSE153679, and GSE182109 datasets were analyzed to identify differentially expressed genes in GBM tissues and cell lines using the limma package in the R software. The GSE182109 dataset was analyzed to determine gene expression at the single-cell levels using the Seurat package in the R software. The TCGA-GTEX, GDSC, CTRP, immunogenetic, and enrichment analyses were performed to study the impact of identified viral HSV1 miRs targets in GBM development. hsv1-miR-H6-3p is upregulated in GBM and can be responsible for EPB41L1 and SH3PXD2A downregulation in GBM tissues. Also, hsv1-miR-H1-5p is upregulated in GBM and can decrease the expression of MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC in GBM development. The single-cell RNA sequencing analyses have demonstrated that MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC are expressed in astrocytes residing in the GBM microenvironment. This study provides novel insights into the potential roles of HSV1 miRs in GBM pathogenesis and offers a reference for further studies on the significance of HSV1 miRs in GBM development.

Evaluation of the antitumor potential of soloxolone tryptamide against glioblastoma multiforme using in silico, in vitro and in vivo approaches

Glioblastoma multiforme (GBM) is a highly aggressive neoplasia characterized by uncontrollable diffusive growth, development of resistance to chemo- and radiotherapy and a high rate of recurrence that leads to low survival of patients with GBM. Given the number of signaling pathways regulating GBM pathogenesis, the development of novel anti-glioblastoma compounds based on multitarget natural metabolites is a promising direction for the study. In the current work, the antitumor potential of semisynthetic triterpenoid soloxolone tryptamide (STA) against human glioblastoma U87 cells was explored. It was found that STA effectively blocked the growth of U87 cells in 2D and 3D culture systems, enhanced the adhesiveness of tumor cells and displayed synergistic cytotoxicity with temozolomide. Performed in silico analysis revealed that the pronounced anti-glioblastoma activity of STA can be explained by its direct interaction with EGFR, ERBB2 and AKT1, which play an important role in the regulation of GBM malignancy. Along with observed direct modulatory action of STA on U87 cells, explored compound had a normalizing effect on the tumor microenvironment in murine heterotopic U87 xenograft model, suppressing the development of immature blood vessels and the production of elastin in tumor tissue. Taken together, obtained results clearly demonstrate that STA can be considered a novel promising antitumor candidate for GMB treatment.

JAK3 Inhibition Regulates Stemness and Thereby Controls Glioblastoma Pathogenesis.

Glioblastoma multiforme (GBM) is the most deadly brain tumor, effective treatment options for which still remain elusive. The current treatment procedure of maximal resection followed by chemotherapy has proved to be grossly insufficient to prevent disease progression and death. Despite best efforts, the maximum survival post-diagnosis is a mere 1.5 years. Therefore, there is a huge unmet clinical need to find effective therapeutic procedures to prevent the pathogenesis and relapse of GBM. Small-molecule inhibitors of signaling pathways are an attractive option to prevent various types of tumors. However, no effective small-molecule inhibitors have been successful against GBM in clinical trials. Various signaling pathways are altered and an array of signaling molecules, transcription factors (TFs), and epigenetic modifying factors have been implicated in the pathogenesis of GBM. JAK-STAT pathway alteration is an important contributor to GBM pathogenesis and relapse. Many small-molecule inhibitors of JAKs, or STAT TFs, especially JAK2 and STAT3, have been assessed for their anti-tumor activity in GBM. However, no definitive success so far has been achieved. Herein, by using two small-molecule inhibitors of JAK3, we show that they are quite effective in inhibiting GBM cell proliferation and neurosphere formation, downregulating their stemness character, and inducing differentiation into neuronal origin cells. The effect of a single treatment with the drugs, both in a serum-containing differentiation medium and in a proliferation medium containing EGF and FGF, was really strong in limiting GBM cell growth, suggesting a potential therapeutic application for these JAK inhibitors in GBM therapy.

Claudin-3 facilitates the progression and mediates the tumorigenic effects of TGF-β in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a significantly malignant and lethal brain tumor with an average survival time of less than 12months. Several researches had shown that Claudin-3 (CLDN3) is overexpressed in various cancers and might be important in their growth and spread. In this study, we used qRT-PCR, western blotting, immunohistochemistry, and immunofluorescence staining assays to investigate the expression levels of various proteins. To explore the proliferation abilities of GBM cells, we conducted the CCK-8 and EdU-DNA formation assays. Wound healing and transwell assays were used to investigate the capacities of invasion and migration of GBM cells. Additionally, we constructed an intracranial xenograft model of GBM to study the in vivo role of CLDN3. Our study devoted to investigate the function of CLDN3 in the pathogenesis and progression of GBM. Our study revealed that CLDN3 was upregulated in GBM and could stimulate tumor cell growth and epithelial-mesenchymal transition (EMT) in both laboratory and animal models. We also discovered that CLDN3 expression could be triggered by transforming growth factor-β (TGF-β) and reduced by specific inhibitors of the TGF-β signaling pathway, such as ITD-1. Further analysis revealed that increased CLDN3 levels enhanced TGF-β-induced growth and EMT in GBM cells, while reducing CLDN3 levels weakened these effects. Our study demonstrated the function of CLDN3 in facilitating GBM growth and metastasis and indicated its involvement in the tumorigenic effects of TGF-β. Developing specific inhibitors of CLDN3 might, therefore, represent a promising new approach for treating this devastating disease.

Transcriptional induction of NF-κB-inducing kinase by E2F4/5 facilitates collective invasion of GBM cells

The prognosis of high-grade gliomas, such as glioblastoma multiforme (GBM), is extremely poor due to the highly invasive nature of these aggressive cancers. Previous work has demonstrated that TNF-weak like factor (TWEAK) induction of the noncanonical NF-κB pathway promotes the invasiveness of GBM cells in an NF-κB-inducing kinase (NIK)-dependent manner. While NIK activity is predominantly regulated at the posttranslational level, we show here that NIK (MAP3K14) is upregulated at the transcriptional level in invading cell populations, with the highest NIK expression observed in the most invasive cells. GBM cells with high induction of NIK gene expression demonstrate characteristics of collective invasion, facilitating invasion of neighboring cells. Furthermore, we demonstrate that the E2F transcription factors E2F4 and E2F5 directly regulate NIK transcription and are required to promote GBM cell invasion in response to TWEAK. Overall, our findings demonstrate that transcriptional induction of NIK facilitates collective cell migration and invasion, thereby promoting GBM pathogenesis.

Identification and characterization of putative biomarkers and therapeutic axis in Glioblastoma multiforme microenvironment.

Non-cellular secretory components, including chemokines, cytokines, and growth factors in the tumor microenvironment, are often dysregulated, impacting tumorigenesis in Glioblastoma multiforme (GBM) microenvironment, where the prognostic significance of the current treatment remains unsatisfactory. Recent studies have demonstrated the potential of post-translational modifications (PTM) and their respective enzymes, such as acetylation and ubiquitination in GBM etiology through modulating signaling events. However, the relationship between non-cellular secretory components and post-translational modifications will create a research void in GBM therapeutics. Therefore, we aim to bridge the gap between non-cellular secretory components and PTM modifications through machine learning and computational biology approaches. Herein, we highlighted the importance of BMP1, CTSB, LOX, LOXL1, PLOD1, MMP9, SERPINE1, and SERPING1 in GBM etiology. Further, we demonstrated the positive relationship between the E2 conjugating enzymes (Ube2E1, Ube2H, Ube2J2, Ube2C, Ube2J2, and Ube2S), E3 ligases (VHL and GNB2L1) and substrate (HIF1A). Additionally, we reported the novel HAT1-induced acetylation sites of Ube2S (K211) and Ube2H (K8, K52). Structural and functional characterization of Ube2S (8) and Ube2H (1) have identified their association with protein kinases. Lastly, our results found a putative therapeutic axis HAT1-Ube2S(K211)-GNB2L1-HIF1A and potential predictive biomarkers (CTSB, HAT1, Ube2H, VHL, and GNB2L1) that play a critical role in GBM pathogenesis.

Evaluation of the Antitumor Potential of Soloxolone Tryptamide against Glioblastoma Multiforme Using in silico, in vitro, and in vivo Approaches

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by uncontrollable diffusive growth, resistance to chemo- and radiotherapy, and a high recurrence rate leading to a low survival rate of patients with GBM. Due to a large number of signaling pathways regulating GBM pathogenesis, one of the promising directions is development of novel anti-glioblastoma compounds based on natural metabolites capable of affecting multiple targets. Here, we investigated the antitumor potential of the semisynthetic triterpenoid soloxolone tryptamide (STA) against human glioblastoma U87 cells. STA efficiently blocked the growth of U87 cells in 2D and 3D cultures, enhanced adhesiveness of tumor cells, and displayed synergistic cytotoxicity with temozolomide. In silico analysis suggested that the anti-glioblastoma activity of STA can be explained by its direct interaction with EGFR, ERBB2, and AKT1 which play an important role in the regulation of GBM malignancy. Along with direct effect on U87 cells, STA normalized tumor microenvironment in murine heterotopic U87 xenograft model by suppressing the development of immature blood vessels and elastin production in the tumor tissue. Taken together, our results clearly demonstrate that STA can be a novel promising antitumor candidate for GMB treatment.

The Recent Research Progress of NF-κB Signaling on the Proliferation, Migration, Invasion, Immune Escape and Drug Resistance of Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and invasive primary central nervous system tumor in humans, accounting for approximately 45-50% of all primary brain tumors. How to conduct early diagnosis, targeted intervention, and prognostic evaluation of GBM, in order to improve the survival rate of glioblastoma patients, has always been an urgent clinical problem to be solved. Therefore, a deeper understanding of the molecular mechanisms underlying the occurrence and development of GBM is also needed. Like many other cancers, NF-κB signaling plays a crucial role in tumor growth and therapeutic resistance in GBM. However, the molecular mechanism underlying the high activity of NF-κB in GBM remains to be elucidated. This review aims to identify and summarize the NF-κB signaling involved in the recent pathogenesis of GBM, as well as basic therapy for GBM via NF-κB signaling.

SLC12A5 as a novel potential biomarker of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most prevalent and malignant intracranial tumor with significant features of dismal prognosis and limited therapeutic solutions. Consequently, the present studies are committed to exploring potential biomarkers through bioinformatics analysis, which may serve as valuable prognostic predictors or novel therapeutic targets and provide new insights into the pathogenesis of GBM. We filtered overlapping differentially expressed genes (DEGs) based on expression profilings from three GBM microarray datasets (GSE116520, GSE4290 and GSE68848) and combined RNA sequencing data from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. Hub genes were prioritized from DEGs after performing protein-protein interaction (PPI) network analysis and weighted gene co-expression network analysis (WGCNA). This was followed by survival analysis to identify potential biomarkers among hub genes. Ultimately, the distributions of gene expressions, genetic alterations, upstream regulatory mechanisms and enrichments of gene functions of the identified biomarkers were analysed on public databases. QRT-PCR, immunohistochemical staining and western blotting was also used to confirm the gene expression patterns in GBM and normal brain tissues. CCK-8 assay clarified the effects of the genes on GBM cells. A total of 322 common DEGs were determined and nine genes were subsequently considered as hub genes by the combination of PPI network analysis and WGCNA. Only SLC12A5 had prognostic significance, which was deficient in GBM whereas especially enriched in normal neural tissues. SLC12A5 overexpression would inhibit cell proliferation of U251MG. Genetic alterations of SLC12A5 were rarely seen in GBM patients, and there was no apparent association existed between SLC12A5 expression and DNA methylation. SLC12A5 was prominently involved in ion transport, synapse and neurotransmitter. SLC12A5 shows promise to function as a novel effective biomarker for GBM and deserves further systematic research.