Potential Therapeutic Target For Glioma Research Articles

SERPINF1 Mediates Tumor Progression and Stemness in Glioma.

Serpin family F member 1 (SERPINF1) reportedly plays multiple roles in various tumors; however, its clinical significance and molecular functions in glioma have been largely understudied. In the present study, we analyzed the prognostic value of SERPINF1 in three independent glioma datasets. Next, we explored the molecular functions and transcriptional regulation of SERPINF1 at the single-cell level. Moreover, in vitro experiments were conducted to evaluate the roles of SERPINF1 in the proliferation, invasion, migration, and stemness of glioma cells. Our results showed that a higher expression of SERPINF1 correlated with a poor overall survival rate in glioma patients (hazard ratio: 4.061 in TCGA, 2.017 in CGGA, and 1.675 in GSE16011, p < 0.001). Besides, SERPINF1 knockdown could suppress the proliferation, invasion, and migration of glioma cells in vitro. In addition, SERPINF1 expression was significantly upregulated in glioma stem cells (GSCs) compared to parental glioma cells. Knocking down SERPINF1 impaired the sphere formation of GSC-A172 and GSC-LN18. Bioinformatics analysis revealed that Notch signaling activation was closely associated with high SERPINF1 expression at the single-cell level. Furthermore, STAT1, CREM, and NR2F2 may participate in the transcriptional regulation of SERPINF1 in glioma. Overall, our results suggest that SERPINF1 may be a candidate prognostic predictor and potential therapeutic target for glioma.

The new oncogene transmembrane protein 60 is a potential therapeutic target in glioma.

Glioma is a malignant tumor with a high fatality rate, originating in the central nervous system. Even after standard treatment, the prognosis remains unsatisfactory, probably due to the lack of effective therapeutic targets. The family of transmembrane proteins (TMEM) is a large family of genes that encode proteins closely related to the malicious behavior of tumors. Thus, it is necessary to explore the molecular and clinical characteristics of newly identified oncogenes, such as transmembrane protein 60 (TMEM60), to develop effective treating options for glioma. We used bioinformatic methods and basic experiments to verify the expression of transmembrane protein 60 in gliomas and its relationship with 1p and 19q (1p19q) status, isocitrate dehydrogenase (IDH) status, patient prognosis, and immune cell infiltration using public databases and clinical samples. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to detect co-expressed genes. Thus, we inhibited the expression of transmembrane protein 60 to observe the proliferation and activity of glioma LN229 cells. We found transmembrane protein 60 was significantly upregulated in glioma compared with that in normal brain tissue at the mRNA. In the subgroups of World Health Organization high grade, isocitrate dehydrogenase wildtype, 1p and 19q non-codeletion, or isocitrate dehydrogenase wild combined with 1p and 19q non-codeletion, the expression of transmembrane protein 60 increased, and the prognosis of glioma patients worsened. In the transmembrane protein 60 high expression group, infiltration of immune cells and stromal cells in the tumor microenvironment increased, tumor purity decreased, and immune cells and pathways were activated. The immune cells mainly included regulatory T-cell, gamma delta T-cell, macrophages M0, neutrophils, and CD8+ T-cells. Overexpression of co-inhibitory receptors (CTLA4, PDL1 and CD96) may promote the increase of depletion of T-cell, thus losing the anti-tumor function in the transmembrane protein 60 high expression group. Finally, we found that transmembrane protein 60 silencing weakened the viability, proliferation, and colony formation of glioma LN229 cells. This is the 0 report on the abnormally high expression of transmembrane protein 60 in glioma and its related clinical features, such as tumor microenvironment, immune response, tumor heterogeneity, and patient prognosis. We also found that transmembrane protein 60 silencing weakened the proliferation and colony formation of glioma LN229 cells. Thus, the new oncogene transmembrane protein 60 might be an effective therapeutic target for the clinical treatment of glioma.

Identification of a robust scoring system based on metabolic genes followed by in-depth validation of ATP1A3 in glioma

AimsIn the past few decades, the prognosis of glioma patients has not significantly improved. Therefore, to provide more precise medical services for glioma patients, it is urgent to identify more clinically meaningful subtypes, establish more robust clinical prediction models, and find more effective therapeutic targets. Materials and methodsFour distinct metabolic-associated subtypes were identified by the NMF algorithm based on metabolic genes (MEGs). A robust scoring system was constructed based on the differentially expressed genes (DEGs) screened from the four metabolic-associated subtypes with the LASSO regression algorithm and multivariate Cox regression analysis. Further analysis of scoring systems was done by different R packages. In addition, the ATP1A3 gene was screened and bioinformatics analysis of it was conducted on several public websites. GSEA software was utilized to search hallmark signaling pathways closely related to ATP1A3. Cytological experiments were used to investigate the role of ATP1A3 in the malignant progression of glioblastoma (GBM) cells. Key findingsFour metabolic-associated subtypes with significantly different clinicopathological characteristics were identified, and a robust scoring system with outstanding clinical application value was established. In addition, a tumor suppressor gene ATP1A3 was found, which is expected to be a potential therapeutic target for glioma. SignificanceThis study is of great significance in the diagnosis, prognosis, and prediction of the response to immune checkpoint blockers (ICBs) for glioma patients. More importantly, this study found a potential therapeutic target for glioma.

Expression analysis of human glioma susceptibility gene and P53 in human glioma and its clinical significance based on bioinformatics.

The exact mechanism of glioblastoma multiforme (GBM) remains unclear. This study was to clarify the expression of P53 in glioma and its molecular mechanism, and to explore the possibility of P53 as a potential therapeutic target of glioma and its clinical application value, so as to provide a new theoretical basis for the treatment of glioma. Firstly, a dataset was established to analyze the expression of P53 in different stages of glioma and its relationship with prognosis by using The Cancer Genome Atlas (TCGA) database, RNA-seq data, and survival data of glioma and normal control samples in gene expression profiling and interactive analysis (GEPIA). The genes co-expressed with P53 were screened out, their differential expression between glioma and normal control group was analyzed, and their functions were analyzed by enrichment analysis. The TGGA database was used for data verification and analysis. The correlation between P53 expression and clinicopathological parameters was analyzed. Kaplan-Meier survival analysis was used to analyze the relationship between P53 expression and overall survival (OS) and progression-free survival (PFS) of glioma patients, and Cox regression analysis was used to analyze the independent factors affecting OS and PFS of glioma patients. The results of TCGA data analysis were as follows: The expression level of P53 was different from that of different stages of glioma, namely, the expression level of P53 between grade II and grade III, grade III and grade IV, and grade II and grade IV were significantly different (P<0.05). The results of P53 gene-related survival analysis showed that KNL1 high expression and low expression were significantly different in OS, and the high expression group was associated with poor prognosis (P<0.05). The P53 expression can be an effective biological indicator of poor prognosis of glioma.

Studies on the Therapeutic and Prognostic Biomarkers of Glioma Using a Novel Cuproptosis-Related IncRNA Signature and Validation in Glioma.

Glioma is the most common tumor of the central nervous system (CNS). Drug resistance, and lack of effective treatment methods make the treatment effect of glioma patients unsatisfactory. The recent discovery of cuproptosis has led to new thinking about the therapeutic and prognostic targets of glioma. The transcripts and clinical data of glioma samples were obtained from The cancer genome atlas (TCGA). The cuproptosis-related lncRNA (CRL)-based glioma prognostic models were built through least absolute shrinkage and selection operator (LASSO) regression analysis in the train set and validated in the test set. Kaplan-Meier survival curve, risk curve analysis, and time-dependent receiver operating characteristic (ROC) curve were used to assess the predictive ability and risk differentiation ability of the models. Univariate and multivariate COX regression analyses were conducted on the models and various clinical features, and then nomograms were constructed to verify their predictive efficacy and accuracy. Finally, we explored potential associations of the models with immune function, drug sensitivity, and the tumor mutational burden of glioma. Four CRLs were selected from the training set of 255 LGG samples and the other four CRLs were selected from the training set of 79 GBM samples to construct the models. Follow-up analysis showed that the models have commendable prognostic value and accuracy for glioma. Notably, the models were also associated with the immune function, drug sensitivity, and tumor mutational burden of gliomas. Our study showed that CRLs were prognostic biomarkers of glioma, closely related to glioma immune function. CRLs may affect uniquely the sensitivity of glioma treatment. It will be a potential therapeutic target for glioma. CRLs will offer new perspectives on the prognosis and therapy of gliomas.

Methylation of RARß is a New Clinical Biomarker for Treatment in Higher-grade Gliomas

ABSTRACT Background: The dysregulation of various pathways and cellular processes contributes to the carcinogenic transition from low-grade gliomas to high-grade gliomas. The altered tumor microenvironment, altered epigenetic state, and high mutation heterogeneity are critical factors in glial tumors. The morphogen retinoic acid (RA) controls the homeostasis, regeneration, and development of the brain. RA receptor (RAR) gene methylation has been shown in different types of glial tumors. Aims and Objectives: This study assessed the RARß gene as a potential therapeutic target in gliomas. Materials and Methods: Using in silico methods, potential drugs targeting the RARß gene were compared based on temozolomide’s effectiveness in treating gliomas. Results and Conclusion: Computational techniques can be used to identify drug-mediated pathways. This in silico study holds promise for RARB and RARB-targeted treatment strategies in gliomas.

Migration-inducing gene-7 promotes glioma cell proliferation and invasiveness via activating the MAPK signaling pathway.

Glioma is a highly aggressive primary malignant tumor. Migration-inducing gene-7 (Mig-7) is closely related to tumor invasion and metastasis. However, the detailed molecular mechanism of Mig-7-mediated promotion of glioma cell invasion requires further investigation. Therefore, this study aimed to investigate the molecular mechanism by which Mig-7 promotes invasion and growth of glioma tumor cells. After collecting 65 glioma tissues and 16 non-tumor tissues, the expression difference of Mig-7 between tumor tissues and non-tumor tissues was analyzed. The molecular mechanism of Mig-7 in tumor cells was investigated by knockdown or overexpression of Mig-7 in U87MG cells. Specifically, the expression levels of mitogen-activated protein kinase (MAPK) signaling pathway-related molecules were detected in cells that knocked down Mig-7. MTT, Transwell, and three-dimensional cell culture assays were used to detect the survival, migration, invasion, and tube formation of U87MG cells that overexpressed Mig-7 were treated with the MAPK signaling pathway inhibitors (SP600125, SCH772984, and SB202190). The effect of Mig-7 on the tumorigenic ability of U87MG cells was investigated by subcutaneous tumorigenic experiment in nude mice. The corresponding results indicated that Mig-7 expression was significantly higher in glioma tissues and cell lines compared to that in non-neoplastic brain tissues and normal glial cell lines. In U87MG cells, downregulation or overexpression of Mig-7 inhibited or promoted the expression of MMP-2, MMP-9, LAMC2, EphA2, and VE-cadherin, and phosphorylation levels of ERK1/2, JNK, and p38. Mig-7 overexpression promoted migration, invasion, cell viability, and tube formation, which were reversed by the MAPK signaling pathway inhibitors. Mig-7 overexpression promoted subcutaneous tumor growth in mice and upregulated the phosphorylation levels of ERK1/2, JNK, and p38 and the expression of Ki-67. These effects of Mig-7 overexpression were reversed by MAPK pathway inhibitors. Overall, these results suggest that Mig-7 may be a novel biomarker and potential therapeutic target for glioma, with the MAPK pathway playing a key role in the corresponding Mig-7 mechanism of action.

SLC1A5 enhances malignant phenotypes through modulating ferroptosis status and immune microenvironment in glioma

Glioma is the most common type of primary malignant tumor in the central nervous system with limited treatment satisfaction. Finding new therapeutic targets has remained a major challenge. Ferroptosis is a novel and distinct type of programmed cell death, playing a regulatory role in the progression of tumors. However, the role of ferroptosis or ferroptosis-related genes (FRGs) in glioma progression has not been extensively studied. In our study, a novel ferroptosis-related prognostic model, including 7 genes, was established, in which patients classified into the high-risk group had more immuno-suppressive status and worse prognosis. Among these 7 genes, we screened solute carrier family 1 member 5 (SLC1A5), an FRG, as a possible new target for glioma treatment. Our results showed that the expression of SLC1A5 was significantly upregulated in glioblastoma tissues compared with the low-grade gliomas. In addition, SLC1A5 knockdown could significantly inhibit glioma cell proliferation and invasion, and reduce the sensitivity of ferroptosis via the GPX4-dependent pathway. Furthermore, SLC1A5 was found to be related to immune response and SLC1A5 knockdown decreased the infiltration and M2 polarization of tumor-associated macrophages. Pharmacological inhibition of SLC1A5 by V9302 was confirmed to promote the efficacy of anti-PD-1 therapy. Overall, we developed a novel prognostic model for glioma based on the seven-FRGs signature, which could apply to glioma prognostic and immune status prediction. Besides, SLC1A5 in the model could regulate the proliferation, invasion, ferroptosis and immune state in glioma, and be applied as a prognostic biomarker and potential therapeutic target for glioma.

RPS14 promotes the development and progression of glioma via p53 signaling pathway

Glioma is a common primary intracranial brain disease that exhibits an increasing incidence and mortality rate. Accumulating evidences have suggested that Ribosomal protein S14 (RPS14) was involved in cell proliferation and tumor progression. Nevertheless, the biological function and underlying mechanism of RPS14 in glioma are still largely unclear. Herein, we found that RPS14 was overexpressed in glioma. In the loss-of-function experiments, RPS14 depletion markedly suppressed glioma cell proliferation, migration and prompted cell apoptosis in vitro. Further study suggested that RPS14 depletion inhibited tumor growth of glioma in vivo. Additionally, human phospho-kinase array profiling and Western blot analysis revealed that the effects of RPS14 knockdown on glioma may be closely associated with p53 signaling pathway. Further study indicated that addition of p53 inhibitor pifithrin-α (PFT-α) could attenuate the influences of RPS14 knockdown on cell proliferation and apoptosis. Taken together, our findings suggested that RPS14 exhibits a pro-oncogenic role in glioma progression and may be act as a novel potential therapeutic target for gliomas.

CircRNA circ_POSTN promotes the malignancy of glioma by regulating the miR-433-3p/SPARC axis.

Glioma is a common tumor in the brain. CircRNA hsa_circ_0030018, also termed as hsa_circPOSTN_001 (circ_POSTN), is reported to exert a promoting influence on the development of glioma. Our study intends to deeply explore its regulation mechanism of circ_POSTN. Expression of circ_POSTN, microRNA-433-3p (miR-433-3p) and Secreted protein acidic and rich in cysteine (SPARC) was detected by qRT-PCR or western blot assay. The function of circ_POSTN was analyzed by loss-of-function experiments. The targeting relationship between miR-433-3p and circ_POSTN or SPARC was predicted by bioinformatics analysis and validated by dual-luciferase reporter assay. Xenograft modeling was employed to validate the function of circ_POSTN in glioma in vivo. circ_POSTN and SPARC were upregulated while miR-433-3p was downregulated in glioma tissues and cells. Both circ_POSTN and SPARC knockdown inhibited clonogenicity, migration, and promoted apoptosis of glioma cells. Circ_POSTN sponged miR-433-3p to regulate SPARC expression. Gain of SPARC largely attenuated circ_POSTN knockdown or miR-433-3p overexpression-mediated effects on glioma cell clonogenicity, migration, and apoptosis. Furthermore, silencing of circ_POSTN decreased xenograft tumor growth in vivo. Inhibition of circ_POSTN repressed glioma development, at least in part, via regulating the miR-433-3p/SPARC axis, providing evidence for circ_POSTN as a potential therapeutic target for glioma.

Small Molecule Inhibitors Targeting Transgelin-2-Actin Interaction for Therapeutic Intervention in Glioblastoma

<h3>Purpose/Objective(s)</h3> Glioblastoma (GBM) patients with wild-type <i>IDH1/2</i> experience worse response to the standard treatment due to their invasive phenotype leading to tumor recurrence compared with patients with mutant <i>IDH</i>1/2. In our clinical correlative studies, Transgelin-2 (<i>TAGLN2</i>) was identified as one of the top candidate genes associated with worse patient outcome. Previously, we have shown that <i>TAGLN2</i> is a candidate prognostic biomarker promoting tumorigenesis in human gliomas and a potential therapeutic target for gliomas. Transgelin-2 is known to induce actin polymerization, playing a critical role in cytoskeletal reorganization leading to cell proliferation, migration/invasion, and therapeutic resistance in GBM and other malignancies. However, there is no bonafide pharmacologic inhibitor that specifically blocks the Transgelin-2 functions in cancer. This study aims to target Transgelin-2 by small molecule inhibitors (SMIs) and explore the potential of these SMIs for therapeutic intervention in GBM. <h3>Materials/Methods</h3> Structure-based virtual screening using docking algorithms was used to identify SMIs of Transgelin-2 protein. These compounds were screened for their ability to permeate blood brain barrier (BBB), using SwissADME webtool and <i>in vitro</i> BBB model. A series of <i>in vitro</i> binding assays were performed to measure the binding affinity and kinetics of interaction of the compounds with Transgelin-2 and their potential to inhibit Transgelin-2-dependent actin polymerization. A series of functional assays; Cell proliferation, invasion, neurosphere and clonogenic assays were performed in GBM PDX cell lines to measure the potential of these SMIs to inhibit Transgelin-2-actin mediated functions and their ability to sensitize these cells to Temozolomide (TMZ) and/or radiation therapy (RT). <h3>Results</h3> <i>In silico</i> virtual screening identified 120 Transgelin-2 binding SMIs. Among which forty inhibitors were predicted to penetrate the BBB. Subsequent <i>in vitro</i> binding studies confirmed 12 compounds to bind and inhibit Transgelin-2-dependent actin polymerization. In a series of <i>in vitro</i> assays, these compounds significantly suppressed the growth and invasion of GBM 08-387 and 3359 PDX cell lines. These compounds also showed no significant toxicity to normal human cells. These SMIs also reduced the level of TAGLN2 protein in these cell lines in a dose- and time-dependent fashion. Subsequent <i>in vivo</i> xenograft mouse model experiments are underway to test the BBB permeability, efficacy and toxicity of these select SMIs. Further, the systemic toxicity of these compounds will also be tested in mice. <h3>Conclusion</h3> Our study identified a number of BBB permeable SMIs that specifically bind to TAGLN2 and inhibit its interaction with actin. Importantly, these SMIs suppress cell proliferation and invasion, and sensitize GBM cells to RT and/or TMZ treatment without significant toxicity to normal cells. Altogether, these SMIs of Transgelin-2 may serve as potential candidates for clinical trials.

A Metabolic Plasticity-Based Signature for Molecular Classification and Prognosis of Lower-Grade Glioma

Background: Glioma is one of the major health problems worldwide. Biomarkers for predicting the prognosis of Glioma are still needed. Methods: The transcriptome data and clinic information on Glioma were obtained from the CGGA, TCGA, GDC, and GEO databases. The immune infiltration status in the clusters was compared. The genes with differential expression were identified, and a prognostic model was developed. Several assays were used to detect RPH3A’s role in Glioma cells, including CCK-8, colony formation, wound healing, and transwell migration assay. Results: Lower Grade Glioma (LGG) was divided into two clusters. The immune infiltration difference was observed between the two clusters. We screened for genes that differed between the two groups. WGCNA was used to construct a co-expressed network using the DEGs, and four co-expressed modules were identified, which are blue, green, grey, and yellow modules. High-risk patients have a lower overall survival rate than low-risk patients. In addition, the risk score is associated with histological subtypes. Finally, the role of RPH3A was detected. The overexpression of RPH3A in LGG cells can significantly inhibit cell proliferation and migration and regulate EMT-regulated proteins. Conclusion: Our study developed a metabolic-related model for the prognosis of Glioma cells. RPH3A is a potential therapeutic target for Glioma.

Downregulation of GPR160 inhibits the progression of glioma through suppressing epithelial to mesenchymal transition (EMT) biomarkers.

Glioma is one of the most fatal types of malignant tumours, the cause of which is mostly unknown. Orphan GPCRs (GPRs) have been previously implicated in tumour growth and metastasis. Therefore, these GPRs could prove to be alternative and promising therapeutic targets for cancer treatment. The role of GPR160 in glioma has not yet been assessed. This study aims to explore the association of GPR160 with glioma progression and investigate its role in epithelial-to-mesenchymal transition (EMT) and metastasis. Changes in protein expression were assessed using western blot analysis and immunofluorescent staining assays, while mRNA expression changes were evaluated using qRT-PCR. To detect the changes in progression and metastasis, MTT, EdU proliferation, wound healing, transwell migration, and flow cytometry assays were carried out in vitro. An epithelial to mesenchymal phenotypic analysis was performed to detect EMT. We demonstrated that knockdown of GPR160 inhibited proliferation, colony formation, and cell viability and promoted apoptosis. Pro-apoptotic biomarkers were upregulated, while anti-apoptotic biomarkers were downregulated. Cell lines with GPR160 knockdown (GPR160 KD) showed a slowed migration rate and decreased invasion ability. EMT mesenchymal biomarkers were downregulated in GPR160 KD cell lines, while epithelial biomarkers were upregulated. This study provides evidence that GPR160 is a potential therapeutic target in glioma for the first time. These findings can be used to discover in detail the molecular mechanism and pathways through which GPR160 promotes glioma progression.

The Network of Tumor Microtubes: An Improperly Reactivated Neural Cell Network With Stemness Feature for Resistance and Recurrence in Gliomas.

Gliomas are known as an incurable brain tumor for the poor prognosis and robust recurrence. In recent years, a cellular subpopulation with tumor microtubes (TMs) was identified in brain tumors, which may provide a new angle to explain the invasion, resistance, recurrence, and heterogeneity of gliomas. Recently, it was demonstrated that the cell subpopulation also expresses neural stem cell markers and shares a lot of features with both immature neurons and cancer stem cells and may be seen as an improperly reactivated neural cell network with a stemness feature at later time points of life. TMs may also provide a new angle to understand the resistance and recurrence mechanisms of glioma stem cells. In this review, we innovatively focus on the common features between TMs and sprouting axons in morphology, formation, and function. Additionally, we summarized the recent progress in the resistance and recurrence mechanisms of gliomas with TMs and explained the incurability and heterogeneity in gliomas with TMs. Moreover, we discussed the recently discovered overlap between cancer stem cells and TM-positive glioma cells, which may contribute to the understanding of resistant glioma cell subpopulation and the exploration of the new potential therapeutic target for gliomas.

Differentiated glioma cell-derived fibromodulin activates integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth.

Cancer stem cells (CSCs) alone can initiate and maintain tumors, but the function of non-cancer stem cells (non-CSCs) that form the tumor bulk remains poorly understood. Proteomic analysis showed a higher abundance of the extracellular matrix small leucine-rich proteoglycan fibromodulin (FMOD) in the conditioned medium of differentiated glioma cells (DGCs), the equivalent of glioma non-CSCs, compared to that of glioma stem-like cells (GSCs). DGCs silenced for FMOD fail to cooperate with co-implanted GSCs to promote tumor growth. FMOD downregulation neither affects GSC growth and differentiation nor DGC growth and reprogramming in vitro. DGC-secreted FMOD promotes angiogenesis by activating integrin-dependent Notch signaling in endothelial cells. Furthermore, conditional silencing of FMOD in newly generated DGCs in vivo inhibits the growth of GSC-initiated tumors due to poorly developed vasculature and increases mouse survival. Collectively, these findings demonstrate that DGC-secreted FMOD promotes glioma tumor angiogenesis and growth through paracrine signaling in endothelial cells and identifies a DGC-produced protein as a potential therapeutic target in glioma.

High Expression of CKS2 Predicts Adverse Outcomes: A Potential Therapeutic Target for Glioma.

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a potential prognostic marker and is overexpressed in various cancers. This study analyzed sequencing and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus, with external validation using the Chinese Glioma Genome Atlas (CGGA) data. CKS2 expression in the normal brain and tumor tissue was compared. cBioPortal and MethSurv were utilized to scrutinize the prognostic value of CKS2 methylation. Gene set enrichment examination and single-sample gene set enrichment analysis were employed to explore the potential biological functions of CKS2. Cell viability, colony formation, and transwell assays were conducted to evaluate the influence of CKS2 on glioma cell proliferation and invasion. Compared with normal brain tissue, the expression of CKS2 was upregulated in glioma samples (p < 0.001). Multivariate data analysis from TCGA and CGGA indicated that increased expression of CKS2 was an independent risk factor for the prognosis of overall survival in glioma patients. CKS2 methylation was negatively associated with CKS2 expression. Patients with CKS2 hypomethylation had worse overall survival compared with patients with CKS2 methylation, as suggested by the analysis of both TCGA and CGGA datasets. The expression level of CKS2 is closely related to tumor immunity, including the correlation of tumor immune cell infiltration, immune score, and co-expression of multiple immune-related genes. In addition, CKS2 is associated with several immune checkpoints and responses to the chemotherapy drug cisplatin. CKS2 knockdown impeded the expansion and aggression of glioma cell lines. The changes in CKS2 expression may provide a novel prognostic biomarker that can be used to improve patient overall survival rates.

KAT6B May Be Applied as a Potential Therapeutic Target for Glioma.

Glioma is a prevalent malignancy among brain tumors with high modality and low prognosis. Ferroptosis has been identified to play a crucial role in the progression and treatment of cancers. KAT6B, as a histone acetyltransferase, is involved in multiple cancer development. However, the function of KAT6B in glioma is still elusive. Here, we aimed to evaluate the effect of KAT6B on ferroptosis in glioma cells and explored the potential mechanisms. We observed that the expression of KAT6B was enhanced in clinical glioma samples. The viability of glioma cells was repressed by erastin and the overexpression of KAT6B rescued the phenotype in the cells. Meanwhile, the apoptosis of glioma cells was induced by the treatment of erastin, while the overexpression of KAT6B blocked the effect in the cells. The levels of lipid ROS and iron were promoted by the treatment of erastin and the overexpression of KAT6B could reverse the effect in the cells. Mechanically, we identified that the expression of STAT3 was repressed by the KAT6B knockdown in glioma cells. The KAT6B was able to enrich on the promoter of STAT3 in glioma cells. Meanwhile, ChIP assay showed that the knockdown of KAT6B inhibited the enrichment of histone H3 lysine 23 acetylation (H3K23ac) and RNA polymerase II (RNA pol II) on STAT3 promoter in the cells. Depletion of STAT3 reversed KAT6B-regulated viability, apoptosis, and ferroptosis of glioma cells. Thus, we concluded that KAT6B contributes to glioma progression by repressing ferroptosis via epigenetically inducing STAT3.

PSMC2 is overexpressed in glioma and promotes proliferation and anti-apoptosis of glioma cells

BackgroundThis study aims to investigate the effect of PSMC2 expression on the clinical prognosis of glioma patients and its molecular mechanism.MethodsTCGA multi-tumor screening and survival analysis were combined to explore the differential expression of PSMC2 in multi-tumor. PSMC2 expression in glioma and normal tissues was detected by Western blot and RT-qPCR. Kaplan-Meier survival curve was used to visualize the effect of PSMC2 expression on the overall survival rate and disease-free survival rate of patients with glioma. The highly expressed cell line U343MG was selected to construct a PSMC2 knockdown model by siRNA transfection, and the effect of PSMC2 knockdown on cell proliferation ability was evaluated by CCK-8 assay. Gene-set enrichment analysis of PSMC2 co-expression genes was carried out to predict the molecular mechanism of their regulation of tumor cell phenotypes, and the analysis results were verified by flow cytometry and Western blot.ResultsThrough broad-spectrum screening of 31 kinds of tumors, we found that PSMC2 was upregulated in most tumors, but PSMC2 was most significantly overexpressed in gliomas and correlated with poor prognosis in glioma patients. The results of Western blot and qRT-PCR showed that PSMC2 was significantly overexpressed in glioma tissues. Further survival analysis revealed that the overall survival and disease-free survival of patients with low PSMC2 expression were significantly better than that of patients with high PSMC2 expression. The proliferation of U343MG cells was significantly inhibited after PSMC2 knockdown. Enrichment analysis of PSMC2 co-expression genes indicated that PSMC2 affected the apoptosis process. The expression of apoptosis-related proteins also significantly changed following PSMC2 knockdown.ConclusionsPSMC2 promotes the proliferation of glioma cells and inhibits the apoptosis, which is expected to be a potential therapeutic target for glioma.

PTBP1 is a Novel Poor Prognostic Factor for Glioma.

Objective Polypyrimidine tract-binding protein 1 (PTBP1) is an RNA-binding protein, which plays a role in pre-mRNA splicing and in the regulation of alternative splicing events. However, little was known about the correlation between PTBP1 and glioma and its prognostic significance in glioma patients. Our aim was to investigate the expression, functional role, and prognostic value of PTBP1 in glioma. Methods We explored the expression of PTBP1 protein using immunohistochemistry in 150 adult malignant glioma tissues and 20 normal brain tissues and evaluated its association with clinicopathological parameters by chi-square test. Kaplan-Meier method was used to evaluate the prognostic effect of PTBP1 in glioma. Univariate/multivariate Cox analyses were used to identify independent prognostic factors. Transcriptional regulation network was constructed based on differentially expressed genes (DEGs) of PTBP1 from TCGA/CGGA database. GO and KEGG enrichment analyses were used to explore the function and pathways of DEGs. Results Out of the 150 malignant glioma tissues (60 LGG and 90 GBMs) and 20 normal brain tissues in our cohort, PTBP1 protein was high expressed in glioma tissues (79/150, 52.7%), but no expression was detected in normal brain tissues (0/20, 0%). The expression of PTBP1 was significantly higher in GBMs (P < 0.001). More than half of GBMs (62/90, 68.9%) were PTBP1 high expression. Chi-square test showed that the expression of PTBP1 was correlated with patient age, WHO grade, Ki-67 index, and IDH status. High expression of PTBP1 was significantly associated with poor prognosis in glioma, and it was an independent risk factor in glioma patients. Furthermore, we shed light on the underlying mechanism of PTBP1 by constructing a miR-218-TCF3-PTBP1 transcriptional network in glioma. Conclusion PTBP1 was high expressed in glioma, and it significantly correlated with poor prognosis, suggesting a potential therapeutic target for glioma, particularly for GBM.

LINC00467 facilitates the proliferation, migration and invasion of glioma via promoting the expression of inositol hexakisphosphate kinase 2 by binding to miR-339-3p

ABSTRACT Our previous studies indicate that long noncoding RNA (lncRNA) LINC00467 can act as an oncogene to participate in the malignant progression of glioma, but the underlying molecular mechanism remains to be studied further. This study aimed to explore the biological role of the LINC00467/miR-339-3p/ inositol hexakisphosphate kinase 2 (IP6K2) regulatory axis in glioma. The Cancer Genome Atlas (TCGA), Oncomine databases and reverse transcription‑quantitative PCR (RT‑qPCR) were used to analyze IP6K2 expression in glioma. RT-PCR, EdU and transwell assays were conducted to observe the effect of IP6K2 on glioma cell proliferation, migration and invasion. Using bioinformatics analysis, RT-PCR, and dual luciferase reporter gene assay, the potential role of the LINC00467/miR-339-3p/IP6K2 regulatory axis in glioma was verified. The results showed that IP6K2 was up-regulated in glioma tissues and cell lines. Moreover, the expression level of IP6K2 was correlated with the clinical features of glioma patients. In vitro and in vivo experiments indicated that IP6K2 overexpression could promote the proliferation, migration, and invasion of glioma cells. Further bioinformatics analysis and in vitro assays revealed that LINC00467 could promote IP6K2 expression by binding to miR-339-3p and promote the malignant progression of glioma. Overall, LINC00467 could upregulate IP6K2 by binding to miR-339-3p and promote the proliferation, migration, and invasion of glioma cells. The LINC00467/miR-339-3p/IP6K2 regulatory axis might be a potential therapeutic target for glioma.