Glioma Development Research Articles

NFB-02. Maternal high-fat diet exposure increases the proliferation and glial differentiation of the cells of origin for NF1-optic glioma

Some pediatric cancers arise in the context of tumor predisposition syndromes caused by germline mutations in genes that regulate cell growth. The most common of these syndromes, Neurofibromatosis type 1 (NF1), results in the development of low-grade tumors of the optic pathway (optic pathway gliomas; OPGs) in ~15% of affected children. However, risk assessment for each individual child is difficult, as it is currently challenging to predict which children with NF1 will develop OPG. Emerging human population-based evidence has raised the possibility that patient-specific risk factors, including infant birth weight, may modulate the risk of glioma development. High-infant birth weight can be modeled in mice by maternal exposure to a high-fat high-sucrose (HFHS) diet. To address the hypothesis that maternal high-fat diet exposure will increase the risk of OPG formation through intrinsic effects on the putative tumor cell of origin, we evaluated the effect of maternal exposure to a HFHS diet on the proliferation and differentiation of these cells (neural stem cells within the third ventricular zone; TVZ NSCs). Progeny from obese dams (MatOb) exposed to HFHS diet during and preceding gestation demonstrated increased proliferation and glial differentiation of TVZ NSCs in vivo. Similar results were observed with gestational HFHS diet exposure (GE) that did not result in maternal weight gain, suggesting these effects were related to maternal diet rather than weight. These effects were not observed in NSCs from other regions of the brain, supporting the regional specificity of the effect of diet on these tumor-initiating stem cells. Finally, we found that maternal HFHS diet resulted in elevated levels of leptin and insulin, both of which increase the proliferation of TVZ NSCs. Taken together, these findings provide early experimental evidence that maternal environmental exposure affects developing neural stem cells relevant to the risk of glioma formation.

Transcription factor SNAI2 exerts pro-tumorigenic effects on glioma stem cells via PHLPP2-mediated Akt pathway

The current study aimed to investigate the effects associated with SNAI2 on the proliferation of glioma stem cells (GSCs) to elucidate its underlying molecular mechanism in the development of glioma. The expression of Snail family transcriptional repressor 2 (SNAI2) in glioma tissues was initially predicted via bioinformatics analysis and subsequently confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), which revealed that SNAI2 was highly expressed in glioma tissues as well as GSCs, with an inverse correlation with overall glioma patient survival detected. Loss- and gain- of-function assays were performed to determine the roles of SNAI2 and pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) on GSC viability, proliferation and apoptosis. Data were obtained indicating that SNAI2 promoted the proliferation of GSCs, while overexpressed PHLPP2 brought about a contrasting trend. As detected by chromatin immunoprecipitation, RT-qPCR and agarose gel electrophoresis, SNAI2 bound to the promoter region of PHLPP2 and repressed the transcription of PHLPP2 while SNAI2 was found to inhibit PHLPP2 resulting in activation of the Akt pathway. Finally, the roles of SNAI2 and PHLPP2 were verified in glioma growth in nude mice xenografted with tumor. Taken together, the key findings of the present study suggest that SNAI2 may promote the proliferation of GSCs through activation of the Akt pathway by downregulating PHLPP2.

Overexpression of lncRNA IRAIN restrains the progression and Temozolomide resistance of glioma via repressing IGF-1R-PI3K-NF-κB signaling pathway.

Increasing studies have found that long noncoding RNAs (lncRNAs) contribute to regulating tumor progression. This study explores the expression characteristics, effects, and related mechanisms of lncRNA IGF1R antisense imprinted non-protein coding RNA (IRAIN) in glioma. Quantitative real-time PCR (qRT-PCR) was implemented to testify the IRAIN profile in glioma tissues and paracancerous tissues, and the link between the IRAIN level and the clinicopathological indicators of glioma was analyzed. IRAIN overexpression and knockdown cell models were constructed in glioma cells. Cell proliferation was verified by the colony formation experiment, while flow cytometry was implemented to monitor apoptosis. Transwell assay was performed to examine cell invasion and migration. Western blot (WB) was adopted to compare the profiles of the apoptosis-related proteins (Bax, Bcl2, and Caspase3) and IGF-1R-PI3K-NF-κB pathway. IRAIN was down-regulated in glioma tissues (compared with adjacent normal tissues), and the low IRAIN expression was significantly linked with the larger tumor volume and higher pathological stages. Functionally, overexpressing IRAIN abated glioma cell proliferation, invasion, and migration, promoted apoptosis, and attenuated IGF-1R-PI3K-NF-κB expression and temozolomide (TMZ) resistance, which was also confirmed in the xenograft tumor experiment. The WB result showed that overexpressing IRAIN inactivated the IGF-1R-PI3K-NF-κB pathway. Additionally, the IGF-1R knockdown model was established in U251 cells. Si-IGF-1R induced cell proliferation inhibition, promoted cell death, and reduced cell migration and TMZ resistance, whereas Si-IGF-1R+IRAIN group showed no additional effects on glioma cells compared with the Si-IGF-1R group. IRAIN repressed glioma development and TMZ resistance by inactivating the IGF-1R-PI3K-NF-κB axis.

The Role of Vti1a in Biological Functions and Its Possible Role in Nervous System Disorders.

Vesicle transport through interaction with t-SNAREs 1A (Vti1a), a member of the N-ethylmaleimide-sensitive factor attachment protein receptor protein family, is involved in cell signaling as a vesicular protein and mediates vesicle trafficking. Vti1a appears to have specific roles in neurons, primarily by regulating upstream neurosecretory events that mediate exocytotic proteins and the availability of secretory organelles, as well as regulating spontaneous synaptic transmission and postsynaptic efficacy to control neurosecretion. Vti1a also has essential roles in neural development, autophagy, and unconventional extracellular transport of neurons. Studies have shown that Vti1a dysfunction plays critical roles in pathological mechanisms of Hepatic encephalopathy by influencing spontaneous neurotransmission. It also may have an unknown role in amyotrophic lateral sclerosis. A VTI1A variant is associated with the risk of glioma, and the fusion product of the VTI1A gene and the adjacent TCF7L2 gene is involved in glioma development. This review summarizes Vti1a functions in neurons and highlights the role of Vti1a in the several nervous system disorders.

Hypoxia Promotes Glioma Stem Cell Proliferation by Enhancing the 14-3-3β Expression via the PI3K Pathway.

Glioma is a serious fatal type of cancer with the shorter median survival period and poor quality of living. The overall 5-year survival rate remains low due to high recurrence rates. Glioma stem cells (GSCs) play the important roles in the development of gliomas. Examination of the numerous biomarkers or cancer-associated genes involved in the development or prevention of glioma may therefore serve the discovery of novel strategies to treat patients with glioma. Hypoxia induced by using CoCl2 application and 14-3-3β protein knockdown by specific small interfering RNA transfection were performed in GSCs both in vitro and in vivo to observe their role in glioma progression and metastasis occurrence by using western blot analysis and MTT assay. The results demonstrated that CoCl2 application enhanced the 14-3-3β protein expression and mRNA levels via the PI3K pathway in GSCs. Furthermore, hypoxia promoted GSC cell proliferation and activated the expression of proliferating cell nuclear antigen, which was inhibited following 14-3-3β knockdown. In addition, tumor growth in mice was enhanced by CoCl2 application but reversed following 14-3-3β knockdown, which also enhanced GSC cell apoptosis. In conclusion, the present study demonstrated that hypoxia promoted glioma growth both in vitro and in vivo by increasing the 14-3-3β expression via the PI3K signaling pathway. 14-3-3β and HIF-1α may therefore be considered as the potential therapeutic target to treat patients with glioma.

Olfactory sensory experience regulates gliomagenesis via neuronal IGF1.

Animals constantly receive various sensory stimuli, such as odours, sounds, light and touch, from the surrounding environment. These sensory inputs are essential for animals to search for food and avoid predators, but they also affect their physiological status, and may cause diseases such as cancer. Malignant gliomas-the most lethal form of brain tumour1-are known to intimately communicate with neurons at the cellular level2,3. However, it remains unclear whether external sensory stimuli can directly affect the development of malignant glioma under normal living conditions. Here we show that olfaction can directly regulate gliomagenesis. In an autochthonous mouse model that recapitulates adult gliomagenesis4-6 originating in oligodendrocyte precursor cells (OPCs), gliomas preferentially emerge in the olfactory bulb-the first relay of brain olfactory circuitry. Manipulating the activity of olfactory receptor neurons (ORNs) affects the development of glioma. Mechanistically, olfaction excites mitral and tufted (M/T) cells, which receive sensory information from ORNs and release insulin-like growth factor1 (IGF1) in an activity-dependent manner. Specific knockout of Igf1 in M/T cells suppresses gliomagenesis. In addition, knocking out the IGF1 receptor in pre-cancerous mutant OPCs abolishes the ORN-activity-dependent mitogenic effects. Our findings establish a link between sensory experience and gliomagenesis through their corresponding sensory neuronal circuits.

Protein phosphorylation: A potential target in glioma development.

Glioma is one of the mostcommonprimary brain tumors, and mortality due to this disease is second only to cardiovascular and cerebrovascular diseases. In traditional surgery, it is difficult to eradicate glioma; oftenrecurrence increases its malignant degree, leading to a large number of patients killed by this disease. It is one of the most important subjects to study its pathogenesis and explore effective treatment methods. Research on glioma mechanisms mainly focuses on the effect of DNA methylation in epigenetics. Although there are many studies on protein phosphorylation, there is no overall regulatory mechanism. Protein phosphorylation regulates a variety of cell functions, such as cell growth, division and differentiation, and apoptosis. As a consequence, protein phosphorylation plays a leading part in various activities of glioma, and can also be used as a target to regulate the development of glioma. This review is aimed at studying the effect of protein phosphorylation on glioma, understanding the pathological mechanism, and an in-depth analysis of it. The following is a discussion on glioma growth, migration and invasion, resistance and death in phosphorylation, and the possibility of treating glioma by phosphorylation.

Clinical involvement of Dickkopf protein‐related protein 3 (DKK3) and Prolyloligopeptidase with tumor progression and metastasis onset of Glioblastoma multiforme

Glioma are common malignant brain tumors, among which glioblastoma multiforme (GBM) has the worst prognosis. GBM is characterized by diffuse infiltration of the brain tissue surrounding the bulk of the tumor, associated with chromosomal and genetic mutations that determine the uncontrolled growth of brain cells and tumor cell chemoresistance. Glioblastomas only rarely metastasize to sites outside the central nervous system, for reasons that are poorly understood, however, recent investigations of other tumor types have suggested that particular molecular features may correlate with metastatic potential such as the activation of many angiogenic factors. Aberrant Wnt signaling has been described as a key player in the initiation of and/or maintenance and development of glioma and Dickkopf protein‐related protein 3 (Dkk‐3), as a tumor suppressor, represents the most promising modulators of the Wnt pathway. Moreover, prolyl‐oligopeptidase (PREP) is a serine protease involved in the angiogenesis and inflammatory process and many research studies highlighted the role of this protein in the metastasis spread.The aim of the present study was to evaluate the possible correlation between Dkk‐3 expression and different GBM patients’ parameters in the regulation of tumor growth processes, by investigating the possible role of PREP in GBM‐related metastasis.Biopsies of GBM and GBM‐related metastasis were taken from patients operated at the Neurosurgery of the Polyclinic “G. Martino” of Messina. The study included 20 cases of GBM of different histological grading, taken by female and male patients, aged between 43 to 77 years. The statistical analysis was performed correlating the extent of Dkk‐3 expression of the single GMB samples with different patient parameters: gender, age, survival and % Ki‐67 labeling index as well the evaluation of PREP modulation in GBM‐related metastasis.Clinical data showed that the down‐regulation of Dkk‐3 was correlated with survival and age; specifically, a low expression of Dkk‐3 tends to be higher in male patients compared to female patients, with an age media of 57 years. Instead, the analysis between Dkk‐3 expression and survival after the first GBM surgery did not show a statistically significant correlation. Also, increased reactivity for Ki67 and ATRX was found in biopsies of patients with Dkk‐3 overexpression, associated with an incidence of the mutation in the gene encoding the isocitrate dehydrogenase IDH132. Moreover, a significant PREP expression was found in both GBM primary tumor and GBM‐related metastasis.In conclusion, the overexpression of Dkk‐3 on GBM samples showed a significant reduction of these markers in biopsies of cancer patients compared to controls, while PREP modulation could slow down metastatic expansion by reducing angiogenesis, suggesting new possible molecular targets for future therapeutic protocols.

A Pyroptosis-Related Gene Signature Associated with Prognosis and Tumor Immune Microenvironment in Gliomas

BackgroundPyroptosis is a novel form of cell death that plays a significant role in cancer, while the prognostic values of pyroptosis-related genes in gliomas have not been revealed.MethodsWe analyzed the RNA-seq and clinical data of gliomas from the University of California Santa Cruz (UCSC) Xena database to determine differentially expressed pyroptosis-related genes. Based on these genes, a pyroptosis genes signature was constructed after univariate Cox analysis and Lasso Cox analyses. The sensitivity and specificity of pyroptosis genes signature were verified by the Chinese Glioma Genome Atlas (CGGA) dataset. Finally, we explored the association of risk signatures with tumor microenvironment and immune cell infiltration.ResultsOf 15 differentially expressed pyroptosis-related genes, three genes of BCL2 associated X (BAX), caspase 3 (CASP3), and caspase 4 (CASP4) were used to construct the risk signature. The effectiveness of risk signature for predicting survival at 1, 3, 5 years was performed by the receiver operating characteristic curve (ROC), and the area under curves (AUC) was 0.739, 0.817, and 0.800, respectively. Functional enrichment results showed signal transduction, cell adhesion, immune response, and inflammatory response were enriched. The immune analysis revealed that pyroptosis had a remarkable effect on the immune microenvironment.ConclusionIn this study, we constructed a pyroptosis-related gene signature, which can serve as a potential biomarker for predicting the survival of glioma patients. Additionally, we suggested that pyroptosis may promote gliomas development by inducing chronic inflammation microenvironment.

Inhibition of glioma development by doxorubicin-photochemical internalization generated macrophage vaccine: A survival study in rats

BackgroundThe process known as immunogenic cell death (ICD) is characterized by dead and dying cancer cells exposing and releasing so-called damage associated molecular patterns (DAMPs). ICD has been shown to enhance the efficacy of antigen presenting cell (APC) immunotherapy. Both anthracycline drugs such as doxorubicin (DOX), and photodynamic therapy (PDT) have been shown to be inducers of ICD. It was therefore hypothesized that combined PDT and DOX i.e. photochemical internalization of DOX (DOX-PCI) would increase ICD compared to DOX acting as a single agent. Materials and methodsF98 glioma cells were treated with DOX-PCI in vitro and the ICD markers HMGB1, HSP70, and HSP90 were determined by ELISA assay. Peritoneal macrophages (Ma), obtained from Fisher rats acting as APCs, were co-incubated with dead F98 glioma cells killed via DOX or DOX-PCI treatment ex vivo. The pulsed Ma (Ma DOX or Ma DOX-PCI) were used to inoculate the animals either before (preventive) or after (curative) intra-cranially implantation of the glioma cells. ResultsF98 cells, treated with DOX-PCI in vitro, induced a significantly higher level of HGMB1, HSP70, and HSP90 than DOX acting alone. Ma DOX-PCI inoculated animals, in both preventive and curative protocols, had a pronounced survival benefit compared to either the non-treatment or MaDOX control groups. In the curative protocol, a second booster inoculation significantly improved survival, with 60% of the animals alive at day 60. ConclusionMacrophages primed with DOX-PCI treated glioma cells appeared to be highly effective as APCs and, when injected into host animals, could delay and, in some cases, prevent tumor development.

Long non-coding RNA DDX11-AS1 promotes the proliferation and migration of glioma cells by combining with HNRNPC

Glioma is a malignant tumor of the central nervous system with complex pathogenesis, difficult operation, and a high postoperative recurrence rate. At present, there is still a lack of effective treatment. Long non-coding RNA DDX11 antisense RNA 1 (DDX11-AS1) has been shown to promote tumor development, such as hepatocellular carcinoma, esophageal cancer, etc. However, its molecular mechanism in glioma is poorly understood. In this study, we found that the expression of DDX11-AS1 was elevated in glioma tissues, and patients with high expression of DDX11-AS1 had poor prognosis. DDX11-AS1 was a potential prognostic marker. Functionally, DDX11-AS1 promoted glioma cell proliferation and migration. Mechanistically, DDX11-AS1 interacted with RNA-binding protein heterogeneous nuclear ribonucleoprotein C (HNRNPC) to promote Wnt/β-catenin and AKT pathways and the epithelial-mesenchymal transition process. In summary, our study manifests that the DDX11-AS1/HNRNPC axis may play a vital part in the occurrence and development of glioma, which provides new ideas and therapeutic targets for the diagnosis, treatment, and prognosis of glioma.

TCF3 Induces DNMT1 Expression to Regulate Wnt Signaling Pathway in Glioma.

The epigenetic alteration is widely understood as the key to cancer initiation. Herein, we intended to clarify the role of transcription factor 3 (TCF3) in the development of glioma and the behind epigenetic mechanism. Through bioinformatics analysis, we identified a TCF3-DNA methyltransferase 1 (DNMT1)-secreted frizzled related protein 1 (SFRP1) axis which was differentially expressed and interacted in gliomas. More specifically, TCF3 activated DNMT1 transcription, and DNMT1 repressed SFRP1 expression. TCF3 and DNMT1 were overexpressed, while SFRP1 was downregulated in glioma. Functionally, TCF3 silencing inhibited cell proliferation and migration, and promoted apoptosis, which were reversed by DNMT1. SFRP1 inhibited the tumor supporting effects of DNMT1 on glioma cells. Moreover, TCF3 downregulation or SFRP1 overexpression inhibited tumorigenesis and enhanced apoptosis of glioma cells, while DNMT1 enhanced tumorigenesis and repressed apoptosis in tumor tissues in vivo. The Wnt pathway was a downstream effector of the TCF3-DNMT1-SFRP1 axis. Collectively, this study determined a novel therapeutic target TCF3 for glioma from the perspective of epigenetic alteration via regulation of SFRP1 expression in a DNMT1-dependent manner.

Retraction Note to: Exosomal SNHG16 secreted by CSCs promotes glioma development via TLR7

Retraction Note to: Exosomal SNHG16 secreted by CSCs promotes glioma development via TLR7

Identification of a key glioblastoma candidate gene, FUBP3, based on weighted gene co-expression network analysis

BackgroundGlioblastoma multiforme (GBM) is the most common aggressive malignant brain tumor. However, the molecular mechanism of glioblastoma formation is still poorly understood. To identify candidate genes that may be connected to glioma growth and development, weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between gene sets and clinical characteristics. We also explored the function of the key candidate gene.MethodsTwo GBM datasets were selected from GEO Datasets. The R language was used to identify differentially expressed genes. WGCNA was performed to construct a gene co-expression network in the GEO glioblastoma samples. A custom Venn diagram website was used to find the intersecting genes. The GEPIA website was applied for survival analysis to determine the significant gene, FUBP3. OS, DSS, and PFI analyses, based on the UCSC Cancer Genomics Browser, were performed to verify the significance of FUBP3. Immunohistochemistry was performed to evaluate the expression of FUBP3 in glioblastoma and adjacent normal tissue. KEGG and GO enrichment analyses were used to reveal possible functions of FUBP3. Microenvironment analysis was used to explore the relationship between FUBP3 and immune infiltration. Immunohistochemistry was performed to verify the results of the microenvironment analysis.ResultsGSE70231 and GSE108474 were selected from GEO Datasets, then 715 and 694 differentially expressed genes (DEGs) from GSE70231 and GSE108474, respectively, were identified. We then performed weighted gene co-expression network analysis (WGCNA) and identified the most downregulated gene modules of GSE70231 and GSE108474, and 659 and 3915 module genes from GSE70231 and GSE108474, respectively, were selected. Five intersection genes (FUBP3, DAD1, CLIC1, ABR, and DNM1) were calculated by Venn diagram. FUBP3 was then identified as the only significant gene by survival analysis using the GEPIA website. OS, DSS, and PFI analyses verified the significance of FUBP3. Immunohistochemical analysis revealed FUBP3 expression in GBM and adjacent normal tissue. KEGG and GO analyses uncovered the possible function of FUBP3 in GBM. Tumor microenvironment analysis showed that FUBP3 may be connected to immune infiltration, and immunohistochemistry identified a positive correlation between immune cells (CD4 + T cells, CD8 + T cells, and macrophages) and FUBP3.ConclusionFUBP3 is associated with immune surveillance in GBM, indicating that it has a great impact on GBM development and progression. Therefore, interventions involving FUBP3 and its regulatory pathway may be a new approach for GBM treatment.

Recognition of a Novel Gene Signature for Human Glioblastoma.

Glioblastoma (GBM) is one of the most common malignant and incurable brain tumors. The identification of a gene signature for GBM may be helpful for its diagnosis, treatment, prediction of prognosis and even the development of treatments. In this study, we used the GSE108474 database to perform GSEA and machine learning analysis, and identified a 33-gene signature of GBM by examining astrocytoma or non-GBM glioma differential gene expression. The 33 identified signature genes included the overexpressed genes COL6A2, ABCC3, COL8A1, FAM20A, ADM, CTHRC1, PDPN, IBSP, MIR210HG, GPX8, MYL9 and PDLIM4, as well as the underexpressed genes CHST9, CSDC2, ENHO, FERMT1, IGFN1, LINC00836, MGAT4C, SHANK2 and VIPR2. Protein functional analysis by CELLO2GO implied that these signature genes might be involved in regulating various aspects of biological function, including anatomical structure development, cell proliferation and adhesion, signaling transduction and many of the genes were annotated in response to stress. Of these 33 signature genes, 23 have previously been reported to be functionally correlated with GBM; the roles of the remaining 10 genes in glioma development remain unknown. Our results were the first to reveal that GBM exhibited the overexpressed GPX8 gene and underexpressed signature genes including CHST9, CSDC2, ENHO, FERMT1, IGFN1, LINC00836, MGAT4C and SHANK2, which might play crucial roles in the tumorigenesis of different gliomas.

Phenotypic and molecular states of IDH1 mutation-induced CD24-positive glioma stem-like cells

Mutations in IDH1 and IDH2 drive the development of gliomas. These genetic alterations promote tumor cell renewal, disrupt differentiation states, and induce stem-like properties. Understanding how this phenotypic reprogramming occurs remains an area of high interest in glioma research. Previously, we showed that IDH mutation results in the development of a CD24-positive cell population in gliomas. Here, we demonstrate that this CD24-positive population possesses striking stem-like properties at the molecular and phenotypic levels. We found that CD24 expression is associated with stem-like features in IDH-mutant tumors, a patient-derived gliomasphere model, and a neural stem cell model of IDH1-mutant glioma. In orthotopic models, CD24-positive cells display enhanced tumor initiating potency compared to CD24-negative cells. Furthermore, CD24 knockdown results in changes in cell viability, proliferation rate, and gene expression that closely resemble a CD24-negative phenotype. Our data demonstrate that induction of a CD24-positive population is one mechanism by which IDH-mutant tumors acquire stem-like properties. These findings have significant implications for our understanding of the molecular underpinnings of IDH-mutant gliomas.

Study on the role of transcription factor SPI1 in the development of glioma

BackgroundGlioma is a common malignant brain tumor. The purpose of this study was to investigate the role of the transcription factor SPI1 in glioma.MethodsSPI1 expression in glioma was identified using qRT-PCR and Western blotting. Cell proliferation was assessed using the CCK8 assay. Transwell and wound healing assays were utilized to evaluate cell migration. Additionally, cell cycle and apoptosis were detected using flow cytometry.ResultsWe observed that the expression level of SPI1 was up-regulated in glioma tissues, compared to normal tissues. Furthermore, we found that SPI1 is able to promote proliferation and migration of glioma cells in vitro. Flow cytometry results demonstrate that, compared to si-NC cells, si-SPI1 cells stagnated in the G1 phase, and down-regulation of SPI1 expression is able to increase rates of apoptosis. Double luciferase activity and chromatin immunoprecipitation assay results indicated that SPI1 can bind to the promoter sites and promote the proliferation and migration of glioma cells by regulating the expression of oncogenic PAICS.ConclusionsOur results suggest that SPI1 can promote proliferation and migration of glioma. Furthermore, SPI1 can be utilized as a potential diagnostic marker and therapeutic target for glioma.

Analysis of the Mechanism of RAD18 in Glioma

Introduction: This study aimed to evaluate the regulatory mechanism of RAD18 in glioma development. Methods: RAD18 expression was compared in glioma tumors and normal samples. Furthermore, we investigated the association between gene transcription and clinical factors in glioma samples, followed by functional enrichment analysis, screening for key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, immune infiltration analysis of high and low RAD18 expression groups, and correlation analysis of quantified KEGG signaling pathways and immune cell types. Results: The expression of RAD18 was upregulated in gliomas. Moreover, RAD18 expression was significantly correlated with age, tumor grade, and histological subtype. Notably, patients with gliomas with high RAD18 expression levels had worse overall survival. Functional enrichment analysis showed that RAD18 was significantly related to biological processes, such as cell division, chemical synaptic transmission, and mitotic nuclear division, and KEGG pathways such as cell cycle, oxidative phosphorylation, and extracellular matrix (ECM)-receptor interaction. The infiltration of five immune cells (plasma B cells, naive B cells, resting CD4+ memory T cells, monocytes, and M1 macrophages) was significantly different between the high and low RAD18 expression groups, and this difference was significantly related to key KEGG pathways, such as neuroactive ligand-receptor interaction and ECM-receptor interaction. Conclusion: RAD18 may serve as a target for glioma treatment and as a key regulator of glioma development.

CDC42EP3 promotes glioma progression via regulation of CCND1

Gliomas are the most common brain malignancies characterized by high degree of aggressiveness and high mortality. However, the underlying mechanism of glioma progression remains unclear. Here, we probed the role of CDC42EP3 (CDC42 effector protein 3) played in glioma development and its potential downstream mechanism. The expression of CDC42EP3 in tumor and normal brain tissues were examined through immunohistochemistry and we found the likelihood of CDC42EP3 overexpression was positively correlated with pathological grading. Patients with higher expression of CDC42EP3 were more likely to suffer from recurrence as well. Through constructing CDC42EP3-knockdown cell models, we discovered that silencing CDC42EP3 significantly restricted cell proliferation and migration but facilitated cell apoptosis in vitro. Inhibition on tumor growth mediated by CDC42EP3 depletion was further verified in vivo. Regarding downstream target of CDC42EP3, we found that it may positively regulate the expression of CCND1 through c-Myc-mediated transcription. Furthermore, our findings affirmed that effects of CDC42EP3 overexpression on cell proliferation, migration and apoptosis could be confined by depleting CCND1. In a word, this study reported the tumor-promoting role of CDC42EP3 in glioma progression which probably functioned through targeting CCND1.

Procollagen C-protease enhancer protein is a prognostic factor for glioma and promotes glioma development by regulating multiple tumor-related pathways and immune microenvironment.

ObjectivesGlioma is a common type of brain tumor with high incidence and mortality rates. Procollagen C-protease enhancer protein (PCOLCE) has been shown to regulate tumor growth and metastasis in several cancers. However, the role of PCOLCE in glioma is unknown. This study aims to assess the association between PCOLCE and prognosis of glioma, and investigated the potential mechanisms.MethodsThe prognostic value of PCOLCE was determined using data from nine publicly available glioma cohorts. We also investigated the relationship between PCOLCE and glioma immune microenvironment and predicted response to immunotherapy based on the expression levels of PCOLCE. The potential roles of PCOLCE in glioma were also explored and validated in cell experiment.ResultsSurvival analysis suggested that high-PCOLCE expression was associated with poor prognosis in glioma. Upregulation of PCOLCE enhanced an immune suppressive microenvironment in glioma by regulating immunocyte infiltration and Cancer-Immunity Cycle. Cox and ROC analysis revealed that PCOLCE was a prognostic factor for glioma and could be used to predict survival of the patients. Patients with low-PCOLCE expression were more likely to respond to Immunotherapy with ICI (immune checkpoint inhibitor) and survive longer. Enrichment analysis showed that PCOLCE was associated with multiple tumor-related pathways. Finally, we demonstrated that the knockdown of PCOLCE inhibited glioma development by regulating cell cycle and promoting apoptosis in in vitro experiments.ConclusionPCOLCE promotes glioma progression by regulating multiple tumor-related pathways and immune microenvironment and can be used as a prognostic factor for glioma.