Malignant Progression Of Glioma Research Articles

TRIM6 promotes glioma malignant progression by enhancing FOXO3A ubiquitination and degradation

TRIM6, an E3 ubiquitin ligase with tripartite motif, directly targets protein substrates for degradation through ubiquitination. Studies have shown that TRIM6 plays a significant role in tumor development in various human malignancies. Thus, the aim of this study was to investigate the importance of TRIM6 and its associated mechanism in promoting the progression of glioma. The expression of TRIM6 and its prognostic value in glioma patients were collected from the TCGA and CGGA databases. The effects of TRIM6 on glioma were investigated in vitro by CCK8, colony formation, wound healing, and transwell assays. Co-IP and western blot analysis were used to detect the interaction between TRIM6 and FOXO3A. The effects of TRIM6 were verified in vivo in subcutaneously xenograft models, and tumor size, and immunohistochemical changes were observed. Our analysis of TRIM6 expression in glioma tissues revealed a high level of expression, and the heightened expression of TRIM6 showed a positive correlation with the unfavorable prognosis among glioma/GBM patients. Through loss-of-function and gain-of-function experiments, we observed a profound impact on the proliferation, invasion, and migration abilities of glioma cells both in vitro and in vivo upon deletion of TRIM6. Conversely, the overexpression of TRIM6 intensified the malignant characteristics of glioma. Additionally, our findings revealed a significant interaction between TRIM6 and FOXO3A, wherein TRIM6 contributed to the destabilization of FOXO3A protein by promoting its ubiquitination and subsequent degradation. Experiments conducted in the rescue study affirmed that the promotion of glioma cell proliferation, invasion, and migration is facilitated by TRIM6 through the suppression of FOXO3A protein levels. These observations imply that the TRIM6-FOXO3A axis could potentially serve as an innovative focus for intervening in glioma.

Neutrophils in glioma microenvironment: from immune function to immunotherapy.

Glioma is a malignant tumor of the central nervous system (CNS). Currently, effective treatment options for gliomas are still lacking. Neutrophils, as an important member of the tumor microenvironment (TME), are widely distributed in circulation. Recently, the discovery of cranial-meningeal channels and intracranial lymphatic vessels has provided new insights into the origins of neutrophils in the CNS. Neutrophils in the brain may originate more from the skull and adjacent vertebral bone marrow. They cross the blood-brain barrier (BBB) under the action of chemokines and enter the brain parenchyma, subsequently migrating to the glioma TME and undergoing phenotypic changes upon contact with tumor cells. Under glycolytic metabolism model, neutrophils show complex and dual functions in different stages of cancer progression, including participation in the malignant progression, immune suppression, and anti-tumor effects of gliomas. Additionally, neutrophils in the TME interact with other immune cells, playing a crucial role in cancer immunotherapy. Targeting neutrophils may be a novel generation of immunotherapy and improve the efficacy of cancer treatments. This article reviews the molecular mechanisms of neutrophils infiltrating the central nervous system from the external environment, detailing the origin, functions, classifications, and targeted therapies of neutrophils in the context of glioma.

Phospholipid scramblase 1 acts through the IL-6/JAK/STAT3 pathway to promote the malignant progression of glioma

BackgroundPhospholipid scramblase 1 (PLSCR1) is a calcium-dependent endofacial plasma-membrane protein that plays an essential role in multiple human cancers. However, little is known about its role in glioma. This study aimed to investigate PLSCR1 function in glioma, and elucidate its underlying molecular mechanisms. MethodsPLSCR1 expression in human glioma cell lines (U87MG, U251, LN229, A172 and T98G) and human astrocytes was detected by western blot and qRT-PCR. PLSCR1 was silenced using si-PLSCR1-1 and si-PLSCR1-2 in LN229 and U251 cells. PLSCR1 was overexpressed using the pcDNA-PLSCR1 plasmid in T98G cells. Colony formation, 5-ethynyl-2′-deoxyuridine, flow cytometry and transwell assays were employed for measuring cell proliferation, apoptosis and mobility after PLSCR1 knockdown or overexpression. PLSCR1 function in glycolysis in glioma cells was determined through measuring the extracellular acidification rate, oxygen consumption rate, glucose consumption and lactate production. Besides, immunohistochemistry, western blot and qRT-PCR were utilized to assess mRNA and protein expression. Besides, the effect of PLSCR1 silencing on subcutaneous tumor was also monitored. ResultsPLSCR1 expression was upregulated in glioma. The downregulation of PLSCR1 repressed the proliferation, mobility, epithelial-to-mesenchymal transition (EMT) and glycolysis; however, it facilitated apoptosis in glioma cells. Whereas, PLSCR1 upregulation had the opposite effect. Moreover, PLSCR1 promoted the activation of the IL-6/JAK/STAT3 pathway in glioma cells. Besides, IL-6 treatment significantly reversed the function of PLSCR1 silencing on cell proliferation, mobility, EMT, apoptosis and glycolysis. In a nude mouse tumor model, silencing PLSCR1 suppressed tumor growth via inactivating IL-6/JAK/STAT3 signaling. ConclusionOur results indicated that PLSCR1 could facilitate proliferation, mobility, EMT and glycolysis, but repress apoptosis through activating IL-6/JAK/STAT3 signaling in glioma. Therefore, PLSCR1 may function as a potential therapeutic target for glioma.

Knockdown of PGBD5 inhibits the malignant progression of glioma through upregulation of the PPAR pathway.

Glioma is the most common type of primary intracranial malignant tumor, and because of its high invasiveness and recurrence, its prognosis remains poor. The present study investigated the biological function of piggyBac transportable element derived 5 (PGBD5) in glioma. Glioma and para-cancerous tissues were obtained from five patients. Reverse transcription-quantitative PCR and western blotting were used to detect the expression levels of PGBD5. Transwell assay and flow cytometry were used to evaluate cell migration, invasion, apoptosis and cell cycle distribution. In addition, a nude mouse tumor transplantation model was established to study the downstream pathways of PGBD5 and the molecular mechanism was analyzed using transcriptome sequencing. The mRNA and protein expression levels of PGBD5 were increased in glioma tissues and cells. Notably, knockdown of PGBD5 in vitro could inhibit the migration and invasion of glioma cells. In addition, the knockdown of PGBD5 expression promoted apoptosis and caused cell cycle arrest in the G2/M phase, thus inhibiting cell proliferation. Furthermore, in vivo experiments revealed that knockdown of PGBD5 expression could inhibit Ki67 expression and slow tumor growth. Changes in PGBD5 expression were also shown to be closely related to the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In conclusion, interference with PGBD5 could inhibit the malignant progression of glioma through the PPAR pathway, suggesting that PGBD5 may be a potential molecular target of glioma.

Region-specific DNA hydroxymethylation along the malignant progression of IDH-mutant gliomas.

The majority of low-grade isocitrate dehydrogenase-mutant (IDHmt) gliomas undergo malignant progression (MP), but their underlying mechanism remains unclear. IDHmt gliomas exhibit global DNA methylation, and our previous report suggested that MP could be partly attributed to passive demethylation caused by accelerated cell cycles. However, during MP, there is also active demethylation mediated by ten-eleven translocation, such as DNA hydroxymethylation. Hydroxymethylation is reported to potentially contribute to gene expression regulation, but its role in MP remains under investigation. Therefore, we conducted a comprehensive analysis of hydroxymethylation during MP of IDHmt astrocytoma. Five primary/malignantly progressed IDHmt astrocytoma pairs were analyzed with oxidative bisulfite and the Infinium EPIC methylation array, detecting 5-hydroxymethyl cytosine at over 850,000 locations for region-specific hydroxymethylation assessment. Notably, we observed significant sharing of hydroxymethylated genomic regions during MP across the samples. Hydroxymethylated CpGs were enriched in open sea and intergenic regions (p < 0.001), and genes undergoing hydroxymethylation were significantly associated with cancer-related signaling pathways. RNA sequencing data integration identified 91 genes with significant positive/negative hydroxymethylation-expression correlations. Functional analysis suggested that positively correlated genes are involved in cell-cycle promotion, while negatively correlated ones are associated with antineoplastic functions. Analyses of The Cancer Genome Atlas clinical data on glioma were in line with these findings. Motif-enrichment analysis suggested the potential involvement of the transcription factor KLF4 in hydroxymethylation-based gene regulation. Our findings shed light on the significance of region-specific DNA hydroxymethylation in glioma MP and suggest its potential role in cancer-related gene expression and IDHmt glioma malignancy.

The Significance of the Redox Gene in the Prognosis and Therapeutic Response of Glioma.

Glioblastoma (GBM) is a fatal adult central nervous system tumor. Due to its high heterogeneity, the survival rate and prognosis of patients are poor. Thousands of people die of this disease every year all over the world. At present, the treatment of GBM is mainly through surgical resection and the combination of later drugs, radiotherapy, and chemotherapy. An abnormal redox system is involved in the malignant progression and treatment tolerance of glioma, which is the main reason for poor survival and prognosis. The construction of a GBM redox-related prognostic model may be helpful in improving the redox immunotherapy and prognosis of GBM. Based on glioma transcriptome data and clinical data from The Cancer Genome Atlas, databases, a risk model of redox genes was constructed by univariate and multivariate Cox analysis. The good prediction performance of the model was verified by the internal validation set of The Cancer Genome Atlas, and the external data of Chinese Glioma Genome Atlas. The results confirmed that the higher the risk score, the worse the survival of patients. Age and isocitrate dehydrogenase status were significantly correlated with risk scores. The analysis of immune infiltration and immunotherapy found that there were significant differences in the immune score, matrix score, and ESTIMATE score between high and low-risk groups. reverse transcription polymerase chain reaction and immunohistochemical staining of glioma samples confirmed the expression of the hub gene. Our study suggests that the 5 oxidative-related genes nitricoxidesynthase3, NCF2, VASN, FKBP1B, and TXNDC2 are hub genes, which may provide a reliable prognostic tool for glioma clinical treatment.

NRP1 Induces Enhanced Stemness and Chemoresistance in Glioma Cells via YAP.

Neuropilin-1 (NRP1), a transmembrane glycoprotein, plays an important role in the malignant progression of gliomas; however, its role in chemoresistance is not fully understood. In this study, we observed the effects of NRP1 on the stemness and chemoresistance of glioma cells and the mediating role of Yes-associated protein (YAP). We constructed NRP1 overexpressing LN-229 glioma cells. Cells were treated with recombinant NRP1 protein (rNRP1) and the YAP inhibitor Super-TDU when necessary. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect the sensitivity of cells to temozolomide (TMZ). Sphere and clone formation assays were performed to detect the sphere- and clone-forming abilities of cells. Western blotting was performed to detect cellular CD133, CD44, p-LATS1, and p-YAP protein expression. Immunofluorescence and flow cytometry were used to detect the subcellular localization of YAP and apoptosis, respectively. We found that both NRP1 overexpression and rNRP1 treatment enhanced self-renewal, TMZ resistance, and CD133 and CD44 protein expression in LN-229 cells. NRP1 overexpression and rNRP1 treatment also induced LATS1 and YAP dephosphorylation and YAP nuclear translocation. Super-TDU inhibits NRP1 overexpression-induced enhanced self-renewal and TMZ resistance in LN-229 cells. Our study suggests that NRP1 induces increased stemness in glioma cells, resulting in chemoresistance, and that this effect is associated with YAP activation.

Dishevelled-associated antagonist of β-catenin homolog 3 (DACT3) suppresses glioma progression though Notch1 signaling pathway in β-catenin-dependent manner

The disheveled-associated antagonist of β-catenin homolog 3 (DACT3) has been recognized as a tumor suppressor in various cancers. However, the function of DACT3 on glioma malignant progression along with potential molecular mechanisms is poorly clarified. This research aimed to investigate how DACT3 contributes to suppressing the progression of glioma. In our investigation, a pronounced decrease in DACT3 expression was observed in glioma tissues. Through the overexpression of DACT3, we noted a significant suppression in the proliferation, invasion, and migration of glioma cells, while concurrently observing an increase in cell adhesion. Our exploration into the molecular mechanisms revealed that DACT3 executes its tumor-suppressive role by impeding the expression of notch 1 intracellular domain (NICD) and translocating into the nucleus by downregulating the expression of β-catenin. Consequently, this process leads to the suppression of Notch1 signaling. To summarize, our findings reveal the function of DACT3 to inhibit glioma progression via the Notch1 signaling pathway in β-catenin dependent manner. This study stands as the pioneer in examining the role of DACT3 in glioma progression and comprehensively elucidating its molecular mechanisms in glioma development. Therefore, our results suggest that DACT3 holds promise as both a prognostic factor and a potential biomarker for guiding treatment strategies in glioma patients (Graphical Abstract).

A Transcription Factor ZNF384, Regulated by LINC00265, Activates the Expression of IFI30 to Stimulate Malignant Progression in Glioma.

Glioma remains one of the most challenging primary brain malignancies to treat. Long noncoding RNAs (lncRNAs) and mRNAs (mRNAs) are implicated in regulating the malignant phenotypes of cancers including glioma. This study aimed to elucidate the functions and mechanisms of lncRNA LINC00265 and mRNA IFI30 in the pathogenesis of glioma. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed the upregulated expression of LINC00265 and IFI30 in glioma cells compared to normal human astrocytes. Western blot (WB) quantified the associated proteins. Glioma stemness and epithelial-to-mesenchymal transition (EMT) were assessed by aldehyde dehydrogenase 1 (ALDH1) activity, sphere formation, and WB. Mechanistic and rescue assays evaluated the LINC00265/miR-let-7d-5p/IFI30/ZNF384/IGF2BP2 axis. The results demonstrated that LINC00265 and IFI30 were highly expressed in glioma cells, promoting stemness and EMT. ZNF384 was identified as a transcription factor that upregulates IFI30. Moreover, LINC00265 elevated ZNF384 by sponging miR-let-7d-5p and recruiting IGF2BP2. In conclusion, LINC00265 and IFI30 act as oncogenes in glioma by driving stemness and EMT, underscoring their potential as therapeutic targets.

The promoting effect and mechanism of MAD2L2 on stemness maintenance and malignant progression in glioma

BackgroundGlioblastoma, the most common primary malignant tumor of the brain, is associated with poor prognosis. Glioblastoma cells exhibit high proliferative and invasive properties, and glioblastoma stem cells (GSCs) have been shown to play a crucial role in the malignant behavior of glioblastoma cells. This study aims to investigate the molecular mechanisms involved in GSCs maintenance and malignant progression.MethodsBioinformatics analysis was performed based on data from public databases to explore the expression profile of Mitotic arrest deficient 2 like 2 (MAD2L2) and its potential function in glioma. The impact of MAD2L2 on glioblastoma cell behaviors was assessed through cell viability assays (CCK8), colony formation assays, 5-Ethynyl-2ʹ-deoxyuridine (EDU) incorporation assays, scratch assays, and transwell migration/invasion assays. The findings from in vitro experiments were further validated in vivo using xenograft tumor model. GSCs were isolated from the U87 and LN229 cell lines through flow cytometry and the stemness characteristics were verified by immunofluorescence staining. The sphere-forming ability of GSCs was examined using the stem cell sphere formation assay. Bioinformatics methods were conducted to identified the potential downstream target genes of MAD2L2, followed by in vitro experimental validation. Furthermore, potential upstream transcription factors that regulate MAD2L2 expression were confirmed through chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.ResultsThe MAD2L2 exhibited high expression in glioblastoma samples and showed significant correlation with patient prognosis. In vitro and in vivo experiments confirmed that silencing of MAD2L2 led to decreased proliferation, invasion, and migration capabilities of glioblastoma cells, while decreasing stemness characteristics of glioblastoma stem cells. Conversely, overexpression of MAD2L2 enhanced these malignant behaviors. Further investigation revealed that MYC proto-oncogene (c-MYC) mediated the functional role of MAD2L2 in glioblastoma, which was further validated through a rescue experiment. Moreover, using dual-luciferase reporter gene assays and ChIP assays determined that the upstream transcription factor E2F-1 regulated the expression of MAD2L2.ConclusionOur study elucidated the role of MAD2L2 in maintaining glioblastoma stemness and promoting malignant behaviors through the regulation of c-MYC, suggesting its potential as a therapeutic target.

METTL3-mediated HOTAIRM1 promotes vasculogenic mimicry icontributionsn glioma via regulating IGFBP2 expression

BackgroundHOTAIRM1 is revealed to facilitate the malignant progression of glioma. Vasculogenic mimicry (VM) is critically involved in glioma progression. Nevertheless, the molecular mechanism of HOTAIRM1 in regulating glioma VM formation remains elusive. Thus, we attempted to clarify the role and mechanism of HOTAIRM1 in VM formation in glioma.MethodsqRT-PCR and western blot assays were used to evaluate the gene and protein expression levels of HOTAIRM1 in glioma patient tissue samples and cell lines. The role of HOTAIRM1 in glioma cell progression and VM formation was explored using a series of function gain-and-loss experiments. RNA-binding protein immunoprecipitation (RIP), RNA pull-down, and mechanism experiments were conducted to assess the interaction between HOTAIRM1/METTL3/IGFBP2 axis. Furthermore, rescue assays were conducted to explore the regulatory function of HOTAIRM1/METTL3/IGFBP2 in glioma cell cellular processes and VM formation.ResultsWe found that HOTAIRM1 presented up-regulation in glioma tissues and cells and overexpression of HOTAIRM1 facilitated glioma cell proliferation, migration, invasion, and VM formation. Furthermore, overexpression of HOTAIRM1 promoted glioma tumor growth and VM formation capacity in tumor xenograft mouse model. Moreover, HOTAIRM1 was demonstrated to interact with IGFBP2 and positively regulated IGFBP2 expression. IGFBP2 was found to promote glioma cell malignancy and VM formation. Mechanistically, METTL3 was highly expressed in glioma tissues and cells and was bound with HOTAIRM1 which stabilized HOTAIRM1 expression. Rescue assays demonstrated that METTL3 silencing counteracted the impact of HOTAIRM1 on glioma cell malignancy and VM formation capacity.ConclusionHOTAIRM1, post-transcriptionally stabilized by METTL3, promotes VM formation in glioma via up-regulating IGFBP2 expression, which provides a new direction for glioma therapy.Graphical

TMIC-81. DECODING THE ROLE OF MICROENVIRONMENT ON DISTINCT FAILURE PATTERNS OF MALIGNANT GLIOMAS

Abstract Most malignant gliomas experience recurrence with distinct failure patterns. The spatial relationship between the primary and recurrent tumors usually represents the genomic distanc; however, the molecular backgrounds of these failure patterns have not been evaluated yet. Our aim was to investigate the molecular profiles underlying the distinct failure patterns of malignant gliomas. This study involved 272 malignant glioma patients, with transcriptomic data available for 166 of these cases. The failure pattern was defined according to the spatial relationship between the primary and recurrent pairs including local recurrence, remote recurrence, and leptomeningeal seeding. When the recurrent tumor exhibits more than one failure pattern simultaneously, we define this as a combined failure pattern. Local recurrence was the most frequent pattern, followed by combined failure pattern (62.9% &amp; 22.8%, respectively). Multi-variate cox analysis showed that combined failure pattern was a significant prognostic factor (odds ratio= 3.34, p-value &amp;lt; 0.001). We defined a genomic signature for malignant gliomas with a combined failure pattern (comb-GS) and validated its worse prognostic impact in other cohorts (GLASS, TCGA). Using public scRNA-seq data with regional annotation, we found that two distinct non-tumor components, immune and neuronal components, contributed to the development of the combined failure pattern. This finding was well correlated with the variability of comb-GS in different anatomic regions in IVY-gap dataset. In summary, this study demonstrated that both immune and neuronal components are involved in the progression of malignant gliomas. These two microenvironmental elements exhibit a shared negative clinical outcome, despite presenting distinct phenotype. To decipher the exact biological role of each component, experimental validation is necessary.

CNSC-41. DOES ISCHEMIC STROKE DRIVE BRAIN TUMOR PROGRESSION?

Abstract Glioblastoma multiforme is the most common and lethal primary brain tumor, with a 5-year survival rate of less than 5%. Its complex pathophysiology, highlighted by massive inflammatory responses, enhances tumor progression and impedes therapeutic interventions, leading to its dismal prognosis. Inflammatory responses are also a cardinal feature of brain injury and remarkably, clinical evidence from large-scale patient cohort studies indicates a link between glioma and cerebral ischemic stroke, where approximately 10% of ischemic stroke patients develop glioma. This observation suggests that brain injury may be a risk factor for the development of brain tumors; however, whether and how stroke occurrence promotes brain tumor progression is unknown. To address this knowledge gap, we employed a photothrombotic stroke mouse model in conjunction with established glioma models. In these models, we observed a significant increase in tumor cell proliferation and infiltration towards the infarct region and blood-brain barrier disruption. Intriguingly, spatial transcriptomic analysis in stroke-glioma models highlighted altered pH regulation in the microenvironment at the leading edge of tumor cells near stroke lesions. Further analysis revealed that the astrocytic pH regulator, Slc4a4, is significantly downregulated in the infiltrating tumor cells near infarct lesions, and that Slc4a4 inhibits tumor progression in our glioma models. Based on patient cohort studies that link glioma occurrence with cerebral ischemia and our new mouse model results, our data demonstrates that exposure to cortical ischemia-induced-hypoxia during tumorigenesis, promotes malignant glioma progression by altering the brain microenvironment via pH modulation. These conceptually innovative studies will integrate our new stroke-glioma models and advanced methodologies to investigate the stroke-glioma interaction via hypoxia and pH modulation, potentially identifying new therapy targets.

LncBIRC3-OT promotes the malignant progression of glioma by interacting with RELA to upregulate stanniocalcin-1 expression

Glioma is the most common malignant intracranial tumor, accounting for 80 % of all malignant brain tumors. Growing evidence suggests that lncRNAs are involved in the growth, angiogenesis, metastasis, and therapeutic resistance in a variety of tumors, including glioma. In this study, lncBIRC3-OT (NONHSAT159592.1), which is highly expressed in glioma, was screened by RNA-seq method and verified by quantitative reverse transcription polymerase chain reaction. Subsequently, we knocked down the endogenous expression of lncBIRC3-OT in U87 and U251 cells and found that down-regulated lncBIRC3-OT inhibited cell proliferation, colony formation, migration, and invasion. Mechanically, lncBIRC3-OT could guide RELA protein to the stanniocalcin-1 (STC1) promoter, initiate STC1 transcription, and ultimately promote the progression of glioma. Together, these findings suggest that lncBIRC3-OT is an important regulator promoting glioma progression, and may be a promising therapeutic target for glioma.

SUMOylation of RALY promotes vasculogenic mimicry in glioma cells via the FOXD1/DKK1 pathway

Human malignant gliomas are the most common and aggressive primary malignant tumors of the human central nervous system. Vasculogenic mimicry (VM), which refers to the formation of a tumor blood supply system independently of endothelial cells, contributes to the malignant progression of glioma. Therefore, VM is considered a potential target for glioma therapy. Accumulated evidence indicates that alterations in SUMOylation, a reversible post-translational modification, are involved in tumorigenesis and progression. In the present study, we found that UBA2 and RALY were upregulated in glioma tissues and cell lines. Downregulation of UBA2 and RALY inhibited the migration, invasion, and VM of glioma cells. RALY can be SUMOylated by conjugation with SUMO1, which is facilitated by the overexpression of UBA2. The SUMOylation of RALY increases its stability, which in turn increases its expression as well as its promoting effect on FOXD1 mRNA. The overexpression of FOXD1 promotes DKK1 transcription by activating its promoter, thereby promoting glioma cell migration, invasion, and VM. Remarkably, the combined knockdown of UBA2, RALY, and FOXD1 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. UBA2/RALY/FOXD1/DKK1 axis may play crucial roles in regulating VM in glioma, which may contribute to the development of potential strategies for the treatment of gliomas.

LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines

Leukocyte-associated immunoglobulin-like receptor-1 (LAIR1), an immune receptor containing immunoreceptor tyrosine-based inhibiory motifs (ITIMs), has emerged as an attractive target for cancer therapy. However, the intrinsic function of LAIR1 in gliomas remains unclear. In this study, the poor prognosis of glioma patients and the malignant proliferation of glioma cells in vitro and in vivo were found to be closely correlated with LAIR1. LAIR1 facilitates focal adhesion kinase (FAK) nuclear localization, resulting in increased transcription of cyclin D1 and chemokines/cytokines (CCL5, TGFβ2, and IL33). LAIR1 specifically supports in the immunosuppressive glioma microenvironment via CCL5-mediated microglia/macrophage polarization. SHP2Q510E (PTP domain mutant) or FAKNLM (non-nuclear localizing mutant) significantly reversed the LAIR1-induced growth enhancement in glioma cells. In addition, LAIR1Y251/281F (ITIMs mutant) and SHP2Q510E mutants significantly reduced FAK nuclear localization, as well as CCL5 and cyclin D1 expression. Further experiments revealed that the ITIMs of LAIR1 recruited SH2-containing phosphatase 2 (SHP2), which then interacted with FAK and induced FAK nuclear localization. This study uncovered a critical role for intrinsic LAIR1 in facilitating glioma malignant progression and demonstrated a requirement for LAIR1 and SHP2 to enhance FAK nuclear localization.

HK3 stimulates immune cell infiltration to promote glioma deterioration

BackgroundGlioma is the most common and lethal type of brain tumor, and it is characterized by unfavorable prognosis and high recurrence rates. The reprogramming of energy metabolism and an immunosuppressive tumor microenvironment (TME) are two hallmarks of tumors. Complex and dynamic interactions between neoplastic cells and the surrounding microenvironment can generate an immunosuppressive TME, which can accelerate the malignant progression of glioma. Therefore, it is crucial to explore associations between energy metabolism and the immunosuppressive TME and to identify new biomarkers for glioma prognosis.MethodsIn our work, we analyzed the co-expression relationship between glycolytic genes and immune checkpoints based on the transcriptomic data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) and found the correlation between HK3 expression and glioma tumor immune status. To investigate the biological role of HK3 in glioma, we performed bioinformatics analysis and established a mouse glioblastoma (GBM) xenograft model.ResultsOur study showed that HK3 significantly stimulated immune cell infiltration into the glioma TME. Tissue samples with higher HK3 expressive level showed increasing levels of immune cells infiltration, including M2 macrophages, neutrophils, and various subtypes of activated memory CD4+ T cells. Furthermore, HK3 expression was significantly increasing along with the elevated tumor grade, had a higher level in the mesenchymal subtype compared with those in other subtypes of GBM and could independently predict poor outcomes of GBM patients.ConclusionThe present work mainly concentrated on the biological role of HK3 in glioma and offered a novel insight of HK3 regulating the activation of immune cells in the glioma microenvironment. These findings could provide a new theoretical evidence for understanding the metabolic molecular within the glioma microenvironment and identifying new therapeutic targets.

Function of Long Noncoding RNAs in Glioma Progression and Treatment Based on the Wnt/β-Catenin and PI3K/AKT Signaling Pathways.

Gliomas are a deadly primary malignant tumor of the central nervous system, with glioblastoma (GBM) representing the most aggressive type. The clinical prognosis of GBM patients remains bleak despite the availability of multiple options for therapy, which has needed us to explore new therapeutic methods to face the rapid progression, short survival, and therapy resistance of glioblastomas. As the Human Genome Project advances, long noncoding RNAs (lncRNAs) have attracted the attention of researchers and clinicians in cancer research. Numerous studies have found aberrant expression of signaling pathways in glioma cells. For example, lncRNAs not only play an integral role in the drug resistance process by regulating the Wnt/β-catenin or PI3K/Akt signaling but are also involved in a variety of malignant biological behaviors such as glioma proliferation, migration, invasion, and tumor apoptosis. Therefore, the present review systematically assesses the existing research evidence on the malignant progression and drug resistance of glioma, focusing on the critical role and potential function of lncRNAs in the Wnt/β-catenin and PI3K/Akt classical pathways to promote and encourage further research in this field.

Enhancement of Microglia Functions by Developed Nano-Immuno-Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment.

Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy is explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia "restorer") and D PPA-1 peptide (immune checkpoint blockade) are integrated on a nano-immuno-synergist (D PAM@OA) to work coordinately. The self-assembled OA core is coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which D PPA-1 peptide is attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, D PAM@OA effectively promotes the recruitment and activation of effector T cells by inhibiting aberrant activation of Signal transducer and activator of transcription (STAT-3) pathway in microglia, and assists activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hinders malignant glioma progression and recurrence with or without temozolomide. The work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors.

Focused ultrasound combined with miR-1208-equipped exosomes inhibits malignant progression of glioma.

Exosomes (Exos) can safely and effectively deliver therapeutic substances to glioma cells; however, their blood-brain barrier (BBB) crossing capacity remains limited. Focused ultrasound (FUS) can transiently, reversibly, and locally open the BBB, while the effects of FUS combined with Exos-miRNA on the treatment of glioma have not been explored to date. Exos were extracted by differential centrifugation and the efficacy of miR-1208-loaded Exos combined with FUS in the treatment of glioma was detected by CCK-8, colony formation, flow cytometry, transwell and tumour xenografts assays. The METTL3-mediated regulation of IGF2BP2 on mRNA stability of NUP214 was determined by MeRIP-qPCR, half-life and RIP assays. We used Exos secreted by mesenchymal stem cells as carriers for the tumour suppressor gene miR-1208, and following FUS irradiation, more Exos carrying miR-1208 were allowed to pass through the BBB, and the uptake of miR-1208 in Exos by glioma cells was promoted, thereby achieving high-efficiency tumour-suppressive effects. Furthermore, the molecular mechanism underlying this effect was elucidated that miR-1208 downregulated the m6A methylation level of NUP214 mRNA by negatively regulating the expression of METTL3, thereby NUP214 expression and TGF-β pathway activity were suppressed. MiR-1208-loaded Exos combined with FUS is expected to become an effective glioma treatment and deserves further clinical evaluation.