Prognostic significance of annexin VII expression in glioblastomas multiforme in humans

OBJECT:Glioblastoma multiforme(GBM)is the most common and lethal primary brain tumor in adults.It isnearly uniformly fatal,with a median survival time of approximately l year,despite modem treatment modalities.Nevertheless,a range of survival times exists around this median.Efforts to understand why some patients livelonger or shorter than the average may provide insight into the biology of these neoplasms.The annexin VII(ANX7)gene is located on the human chromosome 10q21,a site long hypothesized to harbor tumor

Nanomedicine-based combination therapies for overcoming temozolomide resistance in glioblastomas

Glioblastoma(GBM)is the most common malignant brain tumor.Although current treatment strategies,including surgery,chemotherapy,and radiotherapy,have achieved clinical effects and prolonged the survival of patients,the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure.Mechanisms underlying the development of resistance involve multiple factors,including drug efflux,DNA damage repair,glioma stem cells,and a hypoxic tumor environment,which are usually correlative and promote each other.As many potential therapeutic targets have been discovered,combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy.In recent years,nanomedicine has revolutionized cancer therapies with optimized accumulation,penetration,internalization,and controlled release.Blood-brain barrier(BBB)penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB.Moreover,different drugs for combination therapy usually process different pharmacokinetics and biodistribution,which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies.Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed.This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.

HSP90B1-mediated plasma membrane localization of GLUT1 promotes radioresistance of glioblastomas

Ionizing radiation is a popular and effective treatment option for glioblastoma(GBM).However,resistance to radiation therapy inevitably occurs during treatment.It is urgent to investigate the mechanisms of radioresistance in GBM and to find ways to improve radiosensitivity.Here,we found that heat shock protein 90 beta family member 1(HSP90B1)was significantly upregulated in radioresistant GBM cell lines.More importantly,HSP90B1 promoted the localization of glucose transporter type 1,a key rate-limiting factor of glycolysis,on the plasma membrane,which in turn enhanced glycolytic activity and subsequently tumor growth and radioresistance of GBM cells.These findings imply that targeting HSP90B1 may effectively improve the efficacy of radiotherapy for GBM patients,a potential new approach to the treatment of glioblastoma.

Impacts of Nutlin-3a and exercise on murine double minute 2-enriched glioma treatment

Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients,with evidence suggesting exercise may reduce mortality risks and aid neural regeneration.The role of the small ubiquitin-like modifier(SUMO)protein,especially post-exercise,in cancer progression,is gaining attention,as are the potential anti-cancer effects of SUMOylation.We used machine learning to create the exercise and SUMO-related gene signature(ESLRS).This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers.We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers,specifically highlighting how murine double minute 2(MDM2),a component of the ESLRS,can be targeted by nutlin-3.This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation.Using comprehensive CRISPR screening,we validated the effects of specific ESLRS genes on low-grade glioma progression.We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation.Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway.Its efficacy decreased with MDM2 overexpression,and this was reversed by Nutlin-3a or exercise.Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation.Notably,both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells.These results suggest the potential for Nutlin-3a,an MDM2 inhibitor,with physical exercise as a therapeutic approach for glioma management.Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise,natural products,and immune regulation in cancer treatment.

Racl＋ cells distributed in accordance with CD 133＋ cells in glioblastomas and the elevated invasiveness of CD 133＋ glioma cells with higher Racl activity

Background Recent studies have suggested that cancer stem cells are one of the major causes for tumor recurrence due to their resistance to radiotherapy and chemotherapy. Although the highly invasive nature of glioblastoma （GBM） cells is also implicated in the failure of current therapies, it is not clear how glioma stem cells （GSCs） are involved in invasiveness. Racl activity is necessary for inducing reorganization of actin cytoskeleton and cell movement. In this study, we aimed to investigate the distribution characteristics of CD133＋ cells and Racl＋ cells in GBM as well as Racl activity in CD133＋ GBM cells, and analyze the migration and invasion potential of these cells. Methods A series of 21 patients with GBM were admitted consecutively and received tumor resection in Tianjin Medical University General Hospital during the first half of the year 2011. Tissue specimens were collected both from the peripheral and the central parts for each tumor under magnetic resonance imaging （MRI） navigation guidance. Immunohistochemical staining was used to detect the CD133＋ cells and Racl＋ cells distribution in GBM specimens. Double-labeling immunofluorescence was further used to analyze CD133 and Racl co-expression and the relationship between CD133＋ cells distribution and Racl expression. Serum-free medium culture and magnetic sorting were used to isolate CD133＋ cells from U87 cell line. Racl activation assay was conducted to assess the activation of Racl in CD133＋ and CD133- U87 cells. The migration and invasive ability of CD133＋ and CD133- U87 cells were determined by cell migration and invasion assays in vitro. Student＇s t-test and one-way analysis of variance （ANOVA） test were used to determine statistical significance in this study. Results In the central parts of GBMs, CD133＋ cells were found to cluster around necrosis and occasionally cluster around the vessels under the microscope by immunohistological staining. In the peripheral parts of the tumors, CD133＋ cells were lined up along the basement membrane of the vessels and myelinated nerve fibers. Racl expression was high and diffused in the central parts of the GBMs, and the Racl＋ cells were distributed basically in accordance with CD133＋ cells both in the central and peripheral parts of GBMs. In double-labeling immunofluorescence, Racl was expressed in （83.14＋4.23）% of CD133＋ cells, and CD133 and Racl co-expressed cells were located around the vessels in GBMs. Significantly higher amounts of Racl-GTP were expressed in the CD133＋ cells （0.378±0.007）, compared to CD133- cells （0.195±0.004） （t=-27.81; P 〈0.05）. CD133＋ cells had stronger ability to migrate （74.34±2.40 vs. 38.72±2.60, t=42.71, P 〈0.005） and invade （52.00±2.28 vs. 31.26±1.82, t=30.76, P 〈0.005）, compared to their counterpart CD133- cells in transwell cell migration/invasion assay. Conclusions These data suggest that CD133＋ GBM cells highly express Racl and have greater potential to migrate and invade through activated Racl-GTP. The accordance of distribution between Racl＋ cells and CD133＋ cells in GBMs implies that Racl might be an inhibited target to prevent invasion and migration and to avoid malignant glioma recurrence

Leveraging Metabolomics to Assess the Next Generation of Temozolomide-based Therapeutic Approaches for Glioblastomas

Glioblastoma multiforme （GBM） is the most common adult primary tumor of the cen- tral nervous system. The current standard of care for glioblastoma patients involves a combination of surgery, radiotherapy and chemotherapy with the alkylating agent temozolomide. Several mech- anisms underlying the inherent and acquired temozolomide resistance have been identified and con- tribute to treatment failure. Early identification of temozolomide-resistant GBM patients and improvement of the therapeutic strategies available to treat this malignancy are of uttermost impor- tance. This review initially looks at the molecular pathways underlying GBM formation and devel- opment with a particular emphasis placed on recent therapeutic advances made in the field. Our focus will next be directed toward the molecular mechanisms modulating temozolomide resistance in GBM patients and the strategies envisioned to circumvent this resistance. Finallyl we highlight the diagnostic and prognostic value of metabolomics in cancers and assess its potential usefulness in improving the current standard of care for GBM patients.

The association between human cytomegalovirus and glioblastomas: a review

Human cytomegalovirus (HCMV) was reported in glioblastoma multiforme (GBM) over a decade ago and this finding has the potential to increase our understanding of the disease and it offers an alternative tumor-specific therapeutic target. Due of this promise, there is a fair amount of time, energy and money being directed towards understanding and utilizing this connection for eventual therapeutic purposes. Nevertheless, the association between GBM and HCMV remains controversial. Several studies have reported conflicting results, further undermining the potential clinical value of this association. In this review, the authors will discuss the latest developments on this evolving issue. Specifically, the results of the latest studies, both positive and negative, will be discussed. Furthermore, potential theories to explain discrepancies reported in the literature will be proposed. Clinical implications including potential targets for anti-HCMV therapy and the latest developments in anti-HCMV therapy will be presented. Finally, solutions to remedy this controversial issue in neuro-oncology will be offered.

Novel approaches to combat chemoresistance against glioblastomas

The poor prognosis of glioblastoma multiforme(GBM)patients is in part due to resistance to current standard-of-care treatments including chemotherapy[predominantly temozolomide(TMZ;Temodar)],radiation therapy and an anti-angiogenic therapy[an antibody against the vascular endothelial growth factor(bevacizumab;Avastin)],resulting in recurrent tumors.Several recurrent GBM tumors are commonly resistant to either TMZ,radiation or bevacizumab,which contributes to the low survival rate for GBM patients.This review will focus on novel targets and therapeutic approaches that are currently being considered to combat GBM chemoresistance.One of these therapeutic options is a small molecule called OKlahoma Nitrone 007(OKN-007),which was discovered to inhibit the transforming growth factor β1 pathway,reduce TMZ-resistance and enhance TMZ-sensitivity.OKN-007 is currently an investigational new drug in clinical trials for both newly-diagnosed and recurrent GBM patients.Another novel target is ELTD1(epidermal growth factor,latrophilin and seven transmembrane domain-containing protein 1;alternatively known as ADGRL4,Adhesion G protein-coupled receptor L4),which we used a monoclonal antibody against,where a therapy against it was found to inhibit Notch 1 in a pre-clinical GBM xenograft model.Notch 1 is known to be associated with chemoresistance in GBM.Other potential therapeutic targets to combat GBM chemoresistance include the phosphoinositide 3-kinase pathway,nuclear factor-κB,the hepatocyte/scatter factor(c-MET),the epidermal growth factor receptor,and the tumor microenvironment.

Resolving the lineage relationship between malignant cells and vascular cells in glioblastomas

Glioblastoma multiforme(GBM),a highly malignant and heterogeneous brain tumor,contains various types of tumor and non-tumor cells.Whether GBM cells can trans-differentiate into non-neural cell types,including mural cells or endothelial cells(ECs),to support tumor growth and invasion remains controversial.Here we generated two genetic GBM models de novo in immunocompetent mouse brains,mimicking essential pathological and molecular features of human GBMs.Lineage-tracing and transplantation studies demonstrated that,although blood vessels in GBM brains underwent drastic remodeling,evidence of trans-differentiation of GBM cells into vascular cells was barely detected.Intriguingly,GBM cells could promiscuously express markers for mural cells during gliomagenesis.Furthermore,single-cell RNA sequencing showed that patterns of copy number variations(CNVs)of mural cells and ECs were distinct from those of GBM cells,indicating discrete origins of GBM cells and vascular components.Importantly,single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages.Rather than expansion owing to trans-differentiation,vascular cell expanded by proliferation during tumorigenesis.Therefore,cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis.Our findings advance understanding of cell lineage dynamics during gliomagenesis,and have implications for targeted treatment of GBMs.

The role of extracellular vesicles in acquisition of resistance to therapy in glioblastomas

Glioblastoma(GBM)is the most aggressive primary brain tumor with a median survival of 15 months despite standard care therapy consisting of maximal surgical debulking,followed by radiation therapy with concurrent and adjuvant temozolomide treatment.The natural history of GBM is characterized by inevitable recurrence with patients dying from increasingly resistant tumor regrowth after therapy.Several mechanisms including inter-and intratumoral heterogeneity,the evolution of therapy-resistant clonal subpopulations,reacquisition of stemness in glioblastoma stem cells,multiple drug efflux mechanisms,the tumor-promoting microenvironment,metabolic adaptations,and enhanced repair of drug-induced DNA damage have been implicated in therapy failure.Extracellular vesicles(EVs)have emerged as crucial mediators in the maintenance and establishment of GBM.Multiple seminal studies have uncovered the multi-dynamic role of EVs in the acquisition of drug resistance.Mechanisms include EV-mediated cargo transfer and EVs functioning as drug efflux channels and decoys for antibody-based therapies.In this review,we discuss the various mechanisms of therapy resistance in GBM,highlighting the emerging role of EV-orchestrated drug resistance.Understanding the landscape of GBM resistance is critical in devising novel therapeutic approaches to fight this deadly disease.

Cyclopeptide moroidin inhibits vasculogenic mimicry formed by glioblastoma cells via regulating β-catenin activation and EMT pathways

Glioblastoma(GBM)is a highly vascularized malignant brain tumor with poor clinical outcomes.Vasculogenic mimicry(VM)formed by aggressive GBM cells is an alternative approach for tumor blood supply and contributes to the failure of anti-angiogenic therapy.To date,there is still a lack of effective drugs that target VM formation in GBM.In the present study,we evaluated the effects of the plant cyclopeptide moroidin on VM formed by GBM cells and investigated its underlying molecular mechanisms.Moroidin significantly suppressed cell migration,tube formation,and the expression levels ofα-smooth muscle actin and matrix metalloproteinase-9 in human GBM cell lines at sublethal concentrations.The RNA sequencing data suggested the involvement of the epithelialmesenchymal transition(EMT)pathway in the mechanism of moroidin.Exposure to moroidin led to a concentration-dependent decrease in the expression levels of the EMT markers N-cadherin and vimentin in GBM cells.Moreover,moroidin significantly reduced the level of phosphorylated extracellular signal-regulated protein kinase(p-ERK)and inhibited the activation of β-catenin.Finally,we demonstrated that the plant cyclopeptide moroidin inhibited VM formation by GBM cells through inhibiting the ERK/β-catenin-mediated EMT.Therefore,our study indicates a potential application of moroidin as an anti-VM agent in the treatment of GBM.

Efficacy and safety of anlotinib combined with the STUPP regimen in patients with newly diagnosed glioblastoma: a multicenter, single-arm, phase Ⅱ trial

Objective:Glioblastomas are highly vascularized malignant tumors.We determined the efficacy and safety of the anti-angiogenic multi-kinase inhibitor,anlotinib,for a newly diagnosed glioblastoma.Methods:This multicenter,single-arm trial(NCT04119674)enrolled 33 treatment-naïve patients with histologically proven glioblastomas between March 2019 and November 2020.Patients underwent treatment with the standard STUPP regimen[fractionated focal irradiation in daily fractions of 1.8-2 Gy given 5 d/w×6 w(total=54-60 Gy)]or radiotherapy plus continuous daily temozolomide(TMZ)(75 mg/m^(2)of body surface area/d,7 d/w from the first to the last day of radiotherapy),followed by 6 cycles of adjuvant TMZ(150-200 mg/m^(2)×5 d during each 28-d cycle)plus anlotinib(8 mg/d on d 1-14 of each 3-w cycle for 2 cycles during concomitant chemoradiotherapy,8 maximal cycles as adjuvant therapy,followed by maintenance at 8 mg/d.The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival(OS)and adverse events(AEs).Results:Thirty-three patients received the planned treatment.The median PFS was 10.9 months(95%CI,9.9-18.7 months)and the 12-month PFS rate was 48.5%.The median OS was 17.4 months(95%CI,14.5-21.1 months)and the 12-month OS rate was 81.8%.The most common AEs included hypertriglyceridemia[58%(n=19)],hypoalbuminemia[46%(n=15)],and hypercholesterolemia[46%(n=15)]during concurrent chemoradiotherapy and leukopenia[73%(n=24)],hypertriglyceridemia[67%(n=22)],and neutropenia[52%(n=17)]during adjuvant therapy.Five patients discontinued treatment due to AEs.HEG1(HR,5.6;95%CI,1.3-23.7;P=0.021)and RP1L1 alterations(HR,11.1;95%CI,2.2-57.2;P=0.004)were associated with a significantly shorter PFS.Conclusions:Anlotinib plus the STUPP regimen has promising anti-tumor activity against glioblastoma and manageable toxicity.HEG1 and RP1L1 alterations might be novel predictive biomarkers of the response to anlotinib.

Comprehensive understanding of glioblastoma molecular phenotypes:classification,characteristics,and transition

Among central nervous system-associated malignancies,glioblastoma(GBM)is the most common and has the highest mortality rate.The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide.In precision medicine,research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity,as well as the refractory nature of GBM toward therapy.Deep understanding of the different molecular expression patterns of GBM subtypes is critical.Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes.The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors.These subtypes also exhibit high plasticity in their regulatory pathways,oncogene expression,tumor microenvironment alterations,and differential responses to standard therapy.Herein,we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype.Furthermore,we review the mesenchymal transition mechanisms of GBM under various regulators.

NUDT5 promotes the growth,metastasis,and Warburg effect of IDH wild-type glioblastoma multiforme cells by upregulating TRIM47

Objective:To explore the regulatory mechanism of NUDT5 in glioblastoma multiforme(GBM).Methods:GEPIA database was used to predict the expressions of NUDT5 and tripartite motif family proteins 47(TRIM47)in GBM patients.RT-qPCR and Western blot analyses were performed to examine NUDT5 expression in GBM cells.LN-229 cell proliferation,migration as well as invasion were estimated by CCK-8,colony formation,wound healing,and Transwell assays following interference with NUDT5.ECAR assay,L-lactic acid kit,glucose detection kit,and ATP detection kit were applied for the detection of glycolysis-related indexes.Co-immunoprecipitation experiment was carried out to verify the relationship between NUDT5 and TRIM47.Results:GEPIA database showed that NUDT5 expression was significantly increased in GBM patients.Inhibiting the expression of NUDT5 in GBM cells significantly suppressed the viability,proliferation,invasion,migration,and glycolysis of GBM cells.Moreover,TRIM47 was highly expressed in GBM cells and interacted with NUDT5.Overexpression of TRIM47 partially reversed the inhibitory effect of NUDT5 downregulation on the proliferation,metastasis,and glycolysis of GBM cells.Conclusions:NUDT5 promotes the growth,metastasis,and Warburg effect of GBM cells by upregulating TRIM47.Both NUDT5 and TRIM47 can be used as targets for GMB treatment.

GRIK1 promotes glioblastoma malignancy and is a novel prognostic factor of poor prognosis

Primary tumors of the central nervous system(CNS)are classified into over 100 different histological types.The most common type of glioma is derived from astrocytes,and the most invasive glioblastoma(WHO IV)accounts for over 57%of these tumors.Glioblastoma(GBM)is the most common and fatal tumor of the CNS,with strong growth and invasion capabilities,which makes complete surgical resection almost impossible.Despite various treatment methods such as surgery,radiotherapy,and chemotherapy,glioma is still an incurable disease,and the median survival time of patients with GBM is shorter than 15 months.Thus,molecular mechanisms of GBM characteristic invasive growth need to be clarified to improve the poor prognosis.Glutamate ionotropic receptor kainate type subunit 1(GRIK1)is essential for brain function and is involved in many mental and neurological diseases.However,GRIK1’s pathogenic roles and mechanisms in GBM are still unknown.Single-nuclear RNA sequencing of primary and recurrent GBM samples revealed that GRIK1 expression was noticeably higher in the recurrent samples.Moreover,immunohistochemical staining of an array of GBM samples showed that high levels of GRIK1 correlated with poor prognosis of GBM,consistent with The Cancer Genome Atlas database.Knockdown of GRIK1 retarded GBM cells growth,migration,and invasion.Taken together,these findings show that GRIK1 is a unique and important component in the development of GBM and may be considered as a biomarker for the diagnosis and therapy in individuals with GBM.

A review on potential heterocycles for the treatment of glioblastoma targeting receptor tyrosine kinases

Glioblastoma,the most aggressive form of brain tumor,poses significant challenges in terms of treatment success and patient survival.Current treatment modalities for glioblastoma include radiation therapy,surgical intervention,and chemotherapy.Unfortunately,the median survival rate remains dishearteningly low at 12–15 months.One of the major obstacles in treating glioblastoma is the recurrence of tumors,making chemotherapy the primary approach for secondary glioma patients.However,the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms.Consequently,considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs.To tackle glioma,numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEKERK-MPAK.By targeting specific signaling pathways,heterocyclic compounds have demonstrated efficacy in glioma therapeutics.Additionally,key kinases including phosphatidylinositol 3-kinase(PI3K),serine/threonine kinase,cytoplasmic tyrosine kinase(CTK),receptor tyrosine kinase(RTK)and lipid kinase(LK)have been considered for investigation.These pathways play crucial roles in drug effectiveness in glioma treatment.Heterocyclic compounds,encompassing pyrimidine,thiazole,quinazoline,imidazole,indole,acridone,triazine,and other derivatives,have shown promising results in targeting these pathways.As part of this review,we propose exploring novel structures with low toxicity and high potency for glioma treatment.The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier.By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics,we can maximize their therapeutic value and minimize adverse effects.Considering the complex nature of glioblastoma,these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.

Targeting brain tumors with innovative nanocarriers:bridging the gap through the blood-brain barrier

Background:Glioblastoma multiforme(GBM)is recognized as the most lethal and most highly invasive tumor.The high likelihood of treatment failure arises fromthe presence of the blood-brain barrier(BBB)and stemcells around GBM,which avert the entry of chemotherapeutic drugs into the tumormass.Objective:Recently,several researchers have designed novel nanocarrier systems like liposomes,dendrimers,metallic nanoparticles,nanodiamonds,and nanorobot approaches,allowing drugs to infiltrate the BBB more efficiently,opening up innovative avenues to prevail over therapy problems and radiation therapy.Methods:Relevant literature for this manuscript has been collected from a comprehensive and systematic search of databases,for example,PubMed,Science Direct,Google Scholar,and others,using specific keyword combinations,including“glioblastoma,”“brain tumor,”“nanocarriers,”and several others.Conclusion:This review also provides deep insights into recent advancements in nanocarrier-based formulations and technologies for GBM management.Elucidation of various scientific advances in conjunction with encouraging findings concerning the future perspectives and challenges of nanocarriers for effective brain tumor management has also been discussed.

ATM Activation is Key in Vasculogenic Mimicry Formation by Glioma Stem-like Cells

Objective Vasculogenic mimicry(VM)is a novel vasculogenic process integral to glioma stem cells(GSCs)in glioblastoma(GBM).However,the relationship between VM and ataxia-telangiectasia mutated(ATM)serine/threonine kinase activation,which confers chemoradiotherapy resistance,remains unclear.Methods We investigated VM formation and phosphorylated ATM(pATM)levels by CD31/GFAPperiodic acid-Schiff dual staining and immunohistochemical staining in 145 GBM specimens.Glioma stem-like cells(GSLCs)derived from the formatted spheres of U87 and U251 cell lines and their pATM level and VM formation ability were examined using western blot and three-dimensional culture.For the examination of the function of pATM in VM formation by GSLCs,ATM knockdown by shRNAs and deactivated via ATM phosphorylation inhibitor KU55933 were studied.Results VM and high pATM expression occurred in 38.5% and 41.8% of tumors,respectively,and were significantly associated with reduced progression-free and overall survival.Patients with VM-positive GBMs exhibited higher pATM levels(r_(s)=0.425,P=0.01).The multivariate analysis established VM as an independent negative prognostic factor(P=0.002).Furthermore,GSLCs expressed high levels of pATM and formed vascular-like networks in vitro.ATM inactivation or knockdown hindered VM-like network formation concomitant with the downregulation of pVEGFR-2,VE-cadherin,and laminin B2.Conclusion VM may predict a poor GBM prognosis and is associated with pATM expression.We propose that pATM promotes VM through extracellular matrix modulation and VE-Cadherin/pVEGFR-2 activation,thereby highlighting ATM activation as a potential target for enhancing anti-angiogenesis therapies for GBM.

Silvestrol alleviates glioblastoma progression through ERK pathway modulation and MANBA and NRG-1 expression

Background:Glioblastoma,a notably malignant tumor within the central nervous system,is distinguished by its aggressive behavior.Silvestrol,a robust inhibitor of the RNA helicase eukaryotic initiation factor 4A(eIF4A),has shown significant potential as an anticancer compound.Yet,the impact of silvestrol on glioblastoma,especially its molecular mechanisms,has not been fully elucidated.Methods:This investigation employed a variety of in vitro assays,such as cell counting kit-8(CCK-8),clonogenic,5-ethynyl-2′-deoxyuridine(EDU),wound healing,and flow cytometry,to evaluate cell cycle progression,apoptosis,cell viability,and migration.Western blot analysis was also performed to study the apoptosis and extracellular regulated kinase(ERK)pathways.After the ERK pathway was inhibited,differentially expressed genes(DEGs)in U87 cells were identified,followed by an analysis of target genes using the gene expression profiling interactive analysis(GEPIA)database.Results:Silvestrol significantly suppressed the proliferation,migration,and colony formation of glioma cells.It caused cell cycle arrest and enhanced apoptosis in these cells.Additionally,silvestrol stimulated the ERK pathway,with these effects being reversible by an ERK phosphorylation inhibitor.Transcriptome combined with GEPIA,GSCA,UALCAN,TIMER database screened 4 potential drug targets of silvestrol:chromosome 1 open reading frame 226(C1ORF226),mannosidase beta A(MANBA),IQ motif and Sec7 domain 2(IQSEC2),neuregulin 1(NRG-1).Among them,C1ORF226 was lower risk gene while MANBA,IQSEC2,and NRG-1 were high-risk genes.Furthermore,silvestrol notably reduced MANBA mRNA levels,which could be reversed by inhibiting ERK phosphorylation.Furthermore,silvestrol markedly decreased NRG-1 protein levels,with an additional reduction observed when the ERK pathway was blocked.Conclusion:Silvestrol’s anti-glioma effects are primarily due to the suppression of MANBA expression via the ERK pathway and possibly by hindering the translation of NRG-1 protein,thus reducing its expression.The downregulation of MANBA and NRG-1 proteins may be crucial in hindering glioma development and progression.These results highlight the intricate relationship between the ERK pathway and gene expression regulation in silvestrol’s therapeutic effectiveness against glioma.

Identification of TMEM159 as a biomarker of glioblastoma progression based on immune characteristics

Background:Glioblastoma multiforme(GBM)is the most general malignancy of the primary central nervous system that is characterized by high aggressiveness and lethality.Transmembrane protein 159(TMEM159)is an endoplasmic reticulum protein that can form oligomers with seipin.The TMEM159-seipin complex decides the site of lipid droplet(LD)formation,and the formation of LDs is a marker of GBM.However,the role of TMEM159 in the progression of GBM has not been investigated to date.Methods:In this study,we examined the genes that may be associated with patient prognosis in GBM by bioinformatics analyses,and identified the key genes that affect the development of GBM using single-cell RNA sequencing technology.The biological functions of TMEM159 in GBM cells were additionally assessed by clone formation and transwell assays as well as using a model of chick embryo chorioallantois membrane(CAM)and western blotting.The association between TMEM159 and epidermal growth factor receptor(EGFR)was finally analyzed in GBM cells.Results:A prognostic model was established and validated for predicting the prognosis.Survival curve analysis showed a critical difference in the prognosis of the high-and low-risk groups predicted by the prognostic model.The results demonstrated that TMEM159 affected the proliferation and invasion of GBM cells.The chick embryo CAM assays demonstrated that the inhibition of TMEM159 expression reduced angiogenesis in the CAM model.Conclusions:The prognostic model achieved good predictive potential for high-risk patients.The findings also revealed that TMEM159 might be an important prognostic factor for GBM,indicating that the protein may be a promising therapeutic target for suppressing the development of GBM.