Malignant Progression Of Glioma Research Articles

Malignant Progression of Diffuse Low-grade Gliomas: A Systematic Review and Meta-analysis on Incidence and Related Factors

Malignant progression of diffuse low-grade glioma (LGG) is a critical event affecting patient survival; however, the incidence and related factors have been inconsistent in literature. According to the PRISMA guidelines, we systematically reviewed articles from 2009, meta-analyzed the incidence of malignant progression, and clarified factors related to the transformation. Forty-one articles were included in this study (n = 7,122; n, number of patients). We identified two definitions of malignant progression: histologically proven (Htrans) and clinically defined (Ctrans). The malignant progression rate curves of Htrans and Ctrans were almost in parallel when constructed from the results of meta-regression by the mean follow-up time. The true transformation rate was supposed to lie between the two curves, approximately 40% at the 10-year mean follow-up. Risk of malignant progression was evaluated using hazard ratio (HR). Pooled HRs were significantly higher in tumors with a larger pre- and postoperative tumor volume, lower degree of resection, and notable preoperative contrast enhancement on magnetic resonance imaging than in others. Oligodendroglial histology and IDH mutation (IDHm) with 1p/19q codeletion (Codel) also significantly reduced the HRs. Using Kaplan-Meier curves from eight studies with molecular data, we extracted data and calculated the 10-year malignant progression-free survival (10yMPFS). The 10yMPFS in patients with IDHm without Codel was 30.4% (95% confidence interval [95% CI]: 22.2-39.0) in Htrans and 38.3% (95% CI: 32.3-44.3) in Ctrans, and that with IDHm with Codel was 71.7% (95% CI: 61.7-79.5) in Htrans and 62.5% (95% CI: 55.9-68.5) in Ctrans. The effect of adjuvant radiotherapy or chemotherapy could not be determined.

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.

Drug repositioning: Using psychotropic drugs for the treatment of glioma.

Psychotropic drugs can penetrate the blood-brain barrier and regulate the levels of neurotransmitters and neuromodulators such as γ-aminobutyric acid, glutamate, serotonin, dopamine, and norepinephrine in the brain, and thus influence neuronal activity. Neuronal activity in the tumor microenvironment can promote the growth and expansion of glioma. There is increasing evidence that in addition to their use in the treatment of mental disorders, antipsychotic, antidepressant, and mood-stabilizing drugs have clinical potential for cancer therapy. These drugs have been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasion/migration or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. In this review, we summarize findings from preclinical and clinical studies investigating the use of antipsychotics, antidepressants, and mood stabilizers in the treatment of various types of cancer, with a focus on glioma; and discuss their presumed antitumor mechanisms. The existing evidence indicates that psychotropic drugs with established pharmacologic and safety profiles can be repurposed as anticancer agents, thus providing new options for the treatment of glioma.

Identification of PYGL as a key prognostic gene of glioma by integrated bioinformatics analysis.

Aim: PYGL has been reported to have carcinogenic effects in a variety of tumors. This study is the first to reveal the relationship between PYGL and the prognosis of glioma. Materials & methods: Analyzing the Chinese Glioma Genome Atlas database, the authors revealed the expression status and prognostic value of PYGL in gliomas and used quantitative real-time PCR to verify PYGL expression again. Subsequently, they used Gene Set Enrichment Analysis to explore the biological pathways that PYGL may participate in. The authors also used the tumor immune estimation resource database to explore the relationship between PYGL and tumor immune cells. Results: PYGL is involved in the malignant progression of glioma. Conclusions: PYGL can be used as a new biomarker and molecular target for evaluating the prognosis and immunotherapy of glioma.

EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3

BackgroundGliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours.MethodsCircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted.ResultsWe identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression.ConclusionsThis work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.

Circ_0001588 Upregulates ERBB4 to Promote Glioma Malignant Progression Through Sponging miR-1281

Circular RNA (circRNA) plays a crucial part in glioma progression. However, the function of circ_0001588 in glioma development is still unknown. The study aims to reveal the role of circ_0001588 in glioma malignant progression and the inner molecular mechanism. The RNA expressions of circ_0001588, microRNA-1281 (miR-1281), and erb-b2 receptor tyrosine kinase 4 (ERBB4) were detected by qRT-PCR. Protein expression was checked by western blot analysis or immunohistochemistry assay. Cell proliferation was investigated by cell counting kit-8 and colony formation assays. Flow cytometry, transwell, and tube formation assays were used to detect cell apoptosis, cell migration, and invasion as well as angiogenesis, respectively. The binding relationship between miR-1281 and circ_0001588 or ERBB4 was identified by dual-luciferase reporter and RNA immunoprecipitation assays. Mouse model assay was performed to confirm the effect of circ_0001588 knockdown on tumor formation in vivo. Circ_0001588 and ERBB4 expressions were significantly upregulated, while miR-1281 was downregulated in glioma tissues and cells compared with control groups. Circ_0001588 expression was closely related to tumor size and WHO grade of glioma. Decreased expression of circ_0001588 in glioma cells led to significant decreases of cell proliferation, migration, invasion, and tube formation and an increase of cell apoptosis. Additionally, downregulation of miR-1281, a target miRNA of circ_0001588, rescued circ_0001588 knockdown-mediated effects. MiR-1281 also inhibited glioma malignant progression by targeting ERBB4. Importantly, circ_0001588 regulated ERBB4 expression by interacting with miR-1281. Furthermore, circ_0001588 depletion suppressed tumor formation in vivo. Circ_0001588 acted as an oncogene in glioma malignant progression by miR-1281/ERBB4 pathway, suggesting the potential of circ_0001588 as a therapeutic target for glioma.

HIF1α/HIF2α induces glioma cell dedifferentiation into cancer stem cells through Sox2 under hypoxic conditions.

Objective: Our previous study showed that glioma stem-like cells could be induced to undergo dedifferentiation under hypoxic conditions, but the mechanism requires further study. HIF1α and HIF2α are the main molecules involved in the response to hypoxia, and Sox2, as a retroelement, plays an important role in the formation of induced pluripotent stem cells, especially in hypoxic microenvironments. Therefore, we performed a series of experiments to verify whether HIF1α, HIF2α and Sox2 regulated glioma cell dedifferentiation under hypoxic conditions.Materials and methods: Sphere formation by single glioma cells was observed, and CD133 and CD15 expression was compared between the normoxic and hypoxic groups. HIF1α, HIF2α, and Sox2 expression was detected using the CGGA database, and the correlation among HIF1α, HIF2α and Sox2 levels was analyzed. We knocked out HIF1α, HIF2α and Sox2 in glioma cells and cultured them under hypoxic conditions to detect CD133 and CD15 expression. The above cells were implanted into mouse brains to analyze tumor volume and survival time.Results: New spheres were formed from single glioma cells in 1% O2, but no spheres were formed in 21% O2. The cells cultured in 1% O2 highly expressed CD133 and CD15 and had a lower apoptosis rate. The CGGA database showed HIF1α and HIF2α expression in glioma. Knocking out HIF1α or HIF2α led to a decrease in CD133 and CD15 expression and inhibited sphere formation under hypoxic conditions. Moreover, tumor volume and weight decreased after HIF1α or HIF2α knockout with the same temozolomide treatment. Sox2 was also highly expressed in glioma, and there was a positive correlation between the HIF1α/HIF2α and Sox2 expression levels. Sox2 was expressed at lower levels after HIF1α or HIF2α was knocked out. Then, Sox2 was knocked out, and we found that CD133 and CD15 expression was decreased. Moreover, a lower sphere formation rate, higher apoptosis rate, lower tumor formation rate and longer survival time after temozolomide treatment were detected in the Sox2 knockout cells.Conclusion: In a hypoxic microenvironment, the HIF1α/HIF2α-Sox2 network induced the formation of glioma stem cells through the dedifferentiation of differentiated glioma cells, thus promoting glioma cell chemoresistance. This study demonstrates that both HIF1α and HIF2α, as genes upstream of Sox2, regulate the malignant progression of glioma through dedifferentiation.

ELK3: A New Molecular Marker for the Diagnosis and Prognosis of Glioma.

ETS transcription factor ELK3 (ELK3), a novel oncogene, affects pathological processes and progression of many cancers in human tissues. However, it remains unclear whether ELK3, as a key gene, affects the pathological process of gliomas and the prognosis of patients with gliomas. This study aimed to comprehensively and systematically reveal the correlation between ELK3 and the malignant progression of gliomas by analyzing clinical sample information stored in multiple databases. We revealed the putative mechanism of ELK3 involvement in malignant gliomas progression and identified a new and efficient biomarker for glioma diagnosis and targeted therapy. Based on the sample data from multiple databases and real-time quantitative polymerase chain reaction (RT-qPCR), the abnormally high expression of ELK3 in gliomas was confirmed. Kaplan-Meier and Cox regression analyses demonstrated that a high ELK3 expression was markedly associated with low patient survival and served as an independent biomarker of gliomas. Wilcox and Kruskal-Wallis tests revealed that expression of ELK3 was positively correlated with several clinical characteristics of patients with gliomas, such as age, WHO classification, and recurrence. Moreover, Cell Counting Kit‐8 (CCK-8), immunofluorescence, and wound healing assays confirmed that ELK3 overexpression markedly promoted the proliferation and migration of glioma cells. Finally, gene set enrichment analysis (GSEA) and western blotting confirmed that overexpression of ELK3 regulated the JAK–STAT signaling pathway and upregulate the expression of signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3 (P-STAT3) to promote the malignant transition of gliomas. Therefore, ELK3 may serve as an efficient biomarker for the diagnosis and prognosis of gliomas and it can also be used as a therapeutic target to improve the poor prognosis of patients with gliomas.

TRAM2 promotes the malignant progression of glioma through PI3K/AKT/mTOR pathway

Molecular biomarkers play an important guidance role in the diagnosis and treatment of glioma. It has been found that TRAM2 (translocation associated membrane protein 2) drives human cancers development. Here we report that TRAM2 activity is required for malignancy properties of glioma. In this study, we demonstrated that TRAM2 is over-expressed in glioma and cell lines, particularly in the mesenchymal subtype, and glioma patients with high expression of TRAM2 is associated with poorer survival. Silencing of TRAM2 significantly suppresses glioma cell proliferation, invasion, migration and EMT in vitro, and inhibits tumorigenicity of glioma cell in vivo. We further identify that TRAM2 is positively associated with activation of the PI3K/AKT/mTOR signaling in glioma. 740Y-P, a PI3K activator, reversed the effects of TRAM2 silencing on glioma cell proliferation, invasion, migration and EMT process. Taken together, these findings establish that TRAM2/PI3K/AKT/mTOR signaling drives malignancy properties of glioma and indicate that TRAM2 may act as a potential therapeutic target for glioma.

CBIO-10. TARGETING HISTONE H4 Lys 20 MONOMETHYLATION IN THE TREATMENT OF GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most malignant primary tumor of the central nervous system, while the pathogenesis remains unclear. Protein lysine methyltransferase SETD8, which is responsible for the modification of histone H4K20me1, has been shown to play an important role in cellular transcriptional regulation and the development of a variety of tumors, yet its role in the malignant progression of GBM has not been elucidated. MATERIAL AND METHODS In the present study, we used primary GBM cell lines, intracranial xenograft model, transcriptome sequencing together with ChIP-sequencing, aiming to elucidate the molecular mechanism of SETD8-mediated H4K20me1 transcriptional regulation in promoting GBM progression. Furthermore, we evaluated the potential therapeutic significance in GBM using SETD8 small molecule inhibitor, UNC0379. RESULTS We found that SETD8 is aberrantly expressed in GBM tissues, accompanied by the dysregulation of H4K20me1 modification, which is associated with tumor pathology and prognosis. Using SETD8 inhibitor UNC0379 or knockdown of SETD8 significantly inhibited GBM cell proliferation in vitro and in vivo, and downregulated H4K20me1 modification level as well as transcriptome expression. CONCLUSION In summary, our work provide a novel insight into the role of SETD8/H4K20me1 axis. SETD8 overexpression mediated aberrant H4K20me1 modification act as a novel "transcriptional switch" in the malignant progression of glioma.

Integrated Analysis of Mutations, miRNA and mRNA Expression in Glioblastoma.

BackgroundGlioblastoma multiforme (GBM) is a common, malignant brain tumor in adults, with a median survival of only 15–23 months. Organisms respond to disease stress through sophisticated mechanisms at the physiological, transcriptional and metabolic levels. However, the molecular regulatory networks responsible for occurrence, progression and recurrence of glioma have yet to be elucidated.MethodsIn this study, we sought to determine the cause of gliomas by developing an RNA-seq technique that analyzes mRNA and small RNA (sRNA) with the aim of discovering potential methods for precisely blocking key signaling pathways in occurrence, progression, and recurrence. The explication of mechanisms leading to GBM formation has become a feasible and promising new therapeutic method.ResultsGBM-associated genes were identified based on their expression during the disease stress response. Analysis of the inverse correlations between microRNAs (miRNAs) and target mRNAs revealed 43 mRNA–miRNA interactions during disease progression. BOC-SMO and BOC-RAS were found to promote the malignant progression of glioma. A total of 3088 differentially expressed genes were identified as involved in several biological processes, such as amino acid metabolism, protein transport associated with immune response, cell proliferation, and cell apoptosis. Fifteen miRNAs were also identified as being differentially expressed in GBM and control groups.ConclusionThe results of this study provide an important foundation for understanding the pathogenesis of glioma and discovering new therapeutic targets.

CRNDE/ETS1/GPR17 Facilitates the Proliferation, Migration, and Invasion of Glioma.

Background Numerous lncRNAs were found as regulatory factors for occurrence and progression of various tumors, but there is still less research on the role of lncRNAs in malignant progression of glioma. Methods Bioinformatics analysis analyzed differential genes (DEGs) in the TCGA database. MTT, flow cytometry, and Transwell assays were performed to test the proliferation, apoptosis, migration, and invasion of cells. qRT-PCR and western blot were conducted to detect RNA and protein expressions of each gene, respectively. CHIP assay verified the binding relationship between genes. FISH assayed subcellar location of CRNDE, and xenograft in nude mice was performed for in vivo verification. Results CRNDE was upregulated in glioma cells, and overexpression of CRNDE facilitated malignant progression of glioma cells. CRNDE regulated occurrence and development of glioma through the CRNDE-ETS1-GPR17 axis. ETS1 was proved to target promoter region of GPR17. Overexpression of CRNDE promoted the binding between ETS1 and the promoter region of GPR17, thus, promoting the transcription of GPR17, while silencing of GPR17 inhibited promotion of CRNDE on proliferation, migration, and invasion of glioma cells. Conclusions These results demonstrated that CRNDE regulated GPR17 expression by binding ETS1, a transcription factor, thereby affecting glioma development. The results also indicated that CRNDE could serve as a possible therapeutic target and prognostic biomarker for glioma.

Bioinformatics analysis reveals a stem cell-expressed circ-Serpine2-mediated miRNA-mRNA regulatory subnetwork in the malignant progression of glioma

BackgroundHigh-grade glioma has a poor prognosis, and GSCs can have pivotal roles in glioma pathology. This study investigated GSC exosome-containing circRNA mechanisms affecting the malignant progression of glioma.MethodsIn this study, we identified differentially expressed circRNAs and constructed a circRNA-miRNA-mRNA regulatory network through circRNA sequencing/bioinformatics analysis. Then, we identified circRNAs that were upregulated in GSC23 cells and employed them as downstream targets in subsequent investigations. Such investigations included downstream target knockout to assess any influence on A172 cell proliferation, invasion, migration and apoptosis. In addition, in vivo investigations using tumor-bearing animals evaluated the in vivo influences of the selected targets.ResultsThis study identified circ-Serpine2/miR-124-3p/KIF20A as a regulatory pathway in glioma. Our in vitro analysis confirmed that circ-Serpine2 could upregulate KIF20A by sponging miR-124-3p, consequently promoting A172 cell proliferation, migration and invasion. Such a signaling channel could also inhibit glioma cell apoptosis. Additionally, our research indicated that circ-Serpine2 inhibited glioma apoptosis and promoted in vivo tumor progression.ConclusionCirc-Serpine2 exacerbated the malignant progression of glioma mediated by the miR-124-3p/KIF20A nexus, thus providing novel predictive/prognostic biomarkers and drug targets against glioma.

Inhibition of FABP6 Reduces Tumor Cell Invasion and Angiogenesis through the Decrease in MMP-2 and VEGF in Human Glioblastoma Cells.

Malignant glioma is one of the most lethal cancers with rapid progression, high recurrence, and poor prognosis in the central nervous system. Fatty acid-binding protein 6 (FABP6) is a bile acid carrier protein that is overexpressed in colorectal cancer. This study aimed to assess the involvement of FABP6 expression in the progression of malignant glioma. Immunohistochemical analysis revealed that FABP6 expression was higher in glioma than in normal brain tissue. After the knockdown of FABP6, a decrease in the migration and invasion abilities of glioma cells was observed. The phosphorylation of the myosin light chain was inhibited, which may be associated with migration ability. Moreover, expression levels of invasion-related proteins, matrix metalloproteinase-2 (MMP-2) and cathepsin B, were reduced. Furthermore, tube formation was inhibited in the human umbilical vein endothelial cells with a decreased concentration of vascular endothelial growth factor (VEGF) in the conditioned medium after the knockdown of FABP6. The phosphorylation of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p65 were also decreased after FABP6 reduction. Finally, the bioluminescent images and immunostaining of MMP-2, cluster of differentiation 31 (CD31), and the VEGF receptor 1 (VEGFR1) revealed attenuated tumor progression in the combination of the FABP6-knocked-down and temozolomide (TMZ)-treated group in an orthotopic xenograft mouse tumor model. This is the first study that revealed the impact of FABP6 on the invasion, angiogenesis, and progression of glioma. The results of this study show that FABP6 may be a potential therapeutic target combined with TMZ for malignant gliomas.

Posttranscriptional inhibition of γ-adducin promotes the proliferation and migration of osteosarcoma cells.

The expression of cytoskeleton-related protein γ-adducin (ADD3) was abnormally reduced in some tumors. Functional experiments demonstrated that it could inhibit the malignant progression of lung cancer and glioma, whereas the involvement of ADD3 in osteosarcoma was not clear. This study aimed to investigate the role of ADD3 in osteosarcoma and its upstream regulatory mechanisms. ADD3 was knocked down by siRNA transfection and the expression level of ADD3 was determined using quantitative real-time PCR assay and Western blot. CCK-8 assay and colony formation were performed to detect the capacity of cell proliferation. Transwell assay and PI and Annexin V-FITC staining were used to determine cell migration and apoptosis, respectively. Luciferase reporter experiment was performed to investigate the interaction between ADD3 and miR-23b-3p. Based on gene silencing assays, we showed that knockdown of ADD3 suppressed apoptosis and promoted the proliferation and migration of osteosarcoma cells, revealing inhibitory effects of ADD3 in osteosarcoma. Luciferase reporter gene assays confirmed that miR-23b-3p could bind to the 3'-UTR of ADD3. Upregulation of miR-23b-3p not only inhibited the expression of ADD3, but also released the tumor suppressive role of ADD3 on the proliferation and migration of osteosarcoma cells. Our study found that ADD3 functioned as a tumor suppressor gene during osteosarcoma development. The abnormal upregulation of miR-23b-3p targeted the expression of ADD3 and resulted in accelerated osteosarcoma cell proliferation and migration. Thus, the miR-23b-3p/ADD3 axis contributes to the development of osteosarcoma and ADD3 is a key driver of malignancy.

SNHG1 Promotes Malignant Progression of Glioma by Targeting miR-140-5p and Regulating PI3K/AKT Pathway [Retraction

[This retracts the article DOI: 10.2147/CMAR.S269572.].

Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma

Glioma, especially the most aggressive type glioblastoma multiforme, is a malignant cancer of the central nervous system with a poor prognosis. Traditional treatments are mainly surgery combined with radiotherapy and chemotherapy, which is still far from satisfactory. Therefore, it is of great clinical significance to find new therapeutic agents. Serving as an inhibitor of differentiation, protein ID2 (inhibitor of DNA binding 2) plays an important role in neurogenesis, neovascularization and malignant development of gliomas. It has been shown that ID2 affects the malignant progression of gliomas through different mechanisms. In this study, a pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations on their ID2 inhibitory activities. Based on the cytotoxicity of these small-molecule compounds, two compounds were shown to effectively inhibit the viability of glioma cells in the micromolar range. Among them, AK-778-XXMU was chosen for further study due to its better solubility in water. A SPR (Surface Plasma Resonance) assay proved the high affinity between AK-778-XXMU and ID2 protein with the KD value as 129 nM. The plausible binding mode of ID2 was studied by molecular docking and it was found to match AGX51 very well in the same binding site. Subsequently, the cancer-suppressing potency of the compound was characterized both in vitro and in vivo. The data demonstrated that compound AK-778-XXMU is a potent ID2 antagonist which has the potential to be developed as a therapeutic agent against glioma.

RNA m1A Methyltransferase TRMT6 Predicts Poorer Prognosis and Promotes Malignant Behavior in Glioma.

Background: Glioma is the most prevalent central nervous system tumor in humans, and its prognosis remains unsatisfactory due to a lack of effective therapeutic targets. The ectopic expression of N1-methyladenosine (m1A) regulators is a key participant in tumorigenesis and progression. However, the m1A regulator expression status, prognostic value, and relationship with tumor clinical features in glioma remain unclear.Methods: Public datasets were used to analyze the mRNA and protein expression levels of m1A regulators. Kaplan–Meier and Cox regression analyses were performed to confirm the prognostic value of m1A regulators in glioma. Cellular experiments were conducted to verify the effect of TRMT6 on cell function. A comprehensive bioinformatics analysis was conducted to identify the potential molecular mechanisms regulated by TEMT6 in glioma.Results: We found that the dysregulation of m1A regulators was closely associated with tumorigenesis and progression in glioma. Furthermore, TRMT6 might be a powerful and independent biomarker for prognosis in glioma. Our study showed that inhibition of TRMT6 suppressed the proliferation, migration, and invasion of glioma cells. Mechanistically, TRMT6 may be involved in glioma progression by regulating cell cycle, PI3K-AKT, TGF-beta, MTORC1, NOTCH, and MYC pathways.Conclusions: Variation in m1A regulators was closely associated with malignant progression in glioma. Silencing TRMT6 suppressed the cell proliferation, migration, and invasion in glioma. m1A regulators, especially TRMT6, might play an essential role in the malignant progression of glioma.

MiR-433-3p Targets AJUBA to Inhibit Malignant Progression of Glioma

Introduction: Glioma is the most aggressive and malignant type of tumors among primary intracranial tumors. miR-433-3p has been verified to be correlated with the formation and progression of many types of cancers. Methods: In this study, the effects of miR-433-3p and AJUBA on the proliferation, migration, and invasion of glioma and the molecular mechanisms were investigated. We analyzed bioinformatics databases and conducted cell biology experiments to determine that compared with adjacent tissue and normal cells, the expression level of miR-433-3p in glioma tissue and cells was lower, while the expression level of AJUBA was higher. Overexpressing miR-433-3p could significantly inhibit the proliferation, migration, and invasion of glioma cells and promote cell apoptosis. Results: In addition, after overexpressing miR-433-3p and AJUBA, it was found that overexpressing AJUBA could attenuate the inhibitory effect of overexpressing miR-433-3p on the proliferation, migration, and invasion of glioma cells, which suggested that miR-433-3p regulated the biological function of glioma by downregulating AJUBA expression. Conclusion: These results proved that miR-433-3p could target to inhibit the expression of AJUBA, thus inhibiting the biological function and malignant progression of glioma.

Cytoskeleton-associated protein 4 (CKAP4) promotes malignant progression of human gliomas through inhibition of the Hippo signaling pathway.

Gliomas are the most common and aggressive malignant brain tumors and are associated with high mortality and incidence in humans. Despite rigorous multi-modal therapy, including surgery, chemotherapy and radiotherapy, patients with malignant glioma survive an average of 12-15months following primary diagnosis. Therefore, new molecular biomarkers are urgently needed for diagnosis and targeted therapy. Here, we find that suppression of CKAP4 might inhibit glioma growth through regulation of Hippo signaling. We examined the expression levels of CKAP4 through analysis of RNA sequencing data from GEPIA and CGGA databases. Then, Lentivirus was used toconstruct stable cell lines with knockout or overexpression of CKAP4. Next, the function of CKAP4 on glioma was investigated in vitro and in an orthotopic brain tumor model in mice. Lastly, luciferase reporter assay, immunofluorescence and immunoblotting were performed to explore the potential mechanism of how CKAP4 affects gliomas. CKAP4 is highly upregulated in glioma and high CKAP4 expressing tumors were associated with poor patient survival. And CKAP4 promotes malignant progression of gliomas via inhibiting Hippo signaling. CKAP4 has potential as a promising biomarker and can predict the prognosis of patients with gliomas. And targeting CKAP4 expression may be an effective therapeutic strategy for the treatment of human gliomas.