Malignant Progression Of Glioma Research Articles

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.

ESPL1 Is a Novel Prognostic Biomarker Associated With the Malignant Features of Glioma.

Research has confirmed that extra spindle pole bodies-like 1 (ESPL1), an etiological factor, promotes the malignant progression of cancers. However, the relationship between ESPL1 and glioma has not yet been demonstrated. The purpose of this study was to reveal the potential mechanisms of ESPL1-mediated malignant glioma progression. Gene expression data and detailed clinical information of glioma cases were obtained from multiple public databases. Subsequently, a series of bioinformatics analyses were used to elucidate the effects of ESPL1 on glioma. The results demonstrated that the mRNA and protein levels of ESPL1 in glioma were higher than those in normal brain tissues. In addition, ESPL1 expression was considerably associated with the clinical and pathological features of gliomas, such as World Health Organization grade, histology, and 1p19q co-deletion status. Importantly, ESPL1 reduced the overall survival (OS) of glioma patients and had prognostic value for gliomas. Gene set enrichment analysis (GSEA) indirectly revealed that ESPL1 regulates the activation of cancer-related pathways, such as the cell cycle and base excision repair pathways. In addition, we used the Connectivity Map (CMap) database to screen three molecular drugs that inhibit ESPL1: thioguanosine, antimycin A, and zidovudine. Finally, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression levels of ESPL1 in glioma cell lines. This study plays an important role in revealing the etiology of glioma by revealing the function of ESPL1, providing a potential molecular marker for the diagnosis and treatment of glioma, especially low-grade glioma.

A Risk Signature Consisting of Eight m6A Methylation Regulators Predicts the Prognosis of Glioma.

Glioma progression seriously correlates to the epigenetic context. This study aims to identify glioma subtypes by clustering analysis of patients using the multi-omics data of N6-methyladenosine (m6A) methylation regulators and to construct a risk signature for investigating the role of m6A methylation regulators in the prognosis of glioma. Multi-omics data of glioma and normal control tissues were obtained through The Cancer Genome Atlas (TCGA) database. The clustering analysis of multi-omics data of patients was conducted using the R package iClusterPlus software. The risk model was constructed by univariate and multivariate Cox analysis, and the glioma expression data and related clinical data were obtained by Chinese Glioma Genome Atlas (CGGA) datasets to verify the risk model. By analyzing the glioma data in TCGA, we found that the risk signature could be constructed according to the eight genes with m6A methylation modification function, including ALKBH5, HNRNPA2B1, IGF2BP2, IGF2BP3, RBM15, WTAP, YTHDF1, and YTHDF2. Meanwhile, we found that IGF2BP2 and IGF2BP3 were highly expressed in glioma subtypes with high-risk scores and closely related to the prognosis of glioma patients. m6A methylation regulators, especially IGF2BP2 and IGF2BP3, play important roles in the malignant progression of glioma. The risk signature constructed by eight m6A methylation regulators can predict the prognosis of glioma. IGF2BP2 and IGF2BP3 may be the key regulatory factors of m6A methylation regulators involved in the occurrence and development of glioma, and can serve as molecular markers for the prognosis of glioma.

WNK3 promotes the invasiveness of glioma cell lines under hypoxia by inducing the epithelial-to-mesenchymal transition.

BackgroundThe primary features of malignant glioma include high rates of mortality and recurrence, uncontrollable invasiveness, strong angiogenesis, and widespread hypoxia. The hypoxic microenvironment is an important factor affecting the malignant progression of glioma. However, the molecular mechanisms underlying glioma adaption in hypoxic microenvironments are poorly understood.ObjectiveThe work presented in this paper focuses on the role of WNK3 gene in glioma invasion under hypoxic conditions. Furthermore, we aim to explore its role in epithelial-to-mesenchymal transition (EMT).MethodsShRNA targeting WNK3 transfection was used to knockdown the WNK3 expression in U87 cells. We used western blot analysis to detect the relative expression of proteins in U87 cells. The effect of WNK3 on cell migration was explored using a transwell assay in the U87 cell line. We also evaluated WNK3 expression levels in glioma samples by immunohistochemistry analysis.ResultsWNK3 expression was significantly higher in high-grade (III and IV) gliomas than in low-grade (I and II) gliomas. WNK3 expression was up-regulated in U87 cells when cultured in a hypoxic environment in addition; WNK3 knockdown inhibited the invasion of U87 glioma cells by regulating the EMT, especially under hypoxic conditions.ConclusionThese findings suggested that WNK3 plays an important role in the hypoxic microenvironment of glioma and might also be a candidate for therapeutic application in the treatment of glioma.

YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m6A modification to activate NF-\u03baB and promote the malignant progression of glioma

BackgroundThe prognosis for diffuse gliomas is very poor and the mechanism underlying their malignant progression remains unclear. Here, we aimed to elucidate the role and mechanism of the RNA N6,2′-O-dimethyladenosine (m6A) reader, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), in regulating the malignant progression of gliomas.MethodsYTHDF2 mRNA levels and functions were assessed using several independent datasets. Western blotting, quantitative polymerase chain reaction, and immunohistochemistry were used to evaluate the expression levels of YTHDF2 and other molecules in human and mouse tumor tissues and cells. Knockdown and overexpression were used to evaluate the effects of YTHDF2, methyltransferase-like 3 (METTL3), and UBX domain protein 1 (UBXN1) on glioma malignancy in cell and orthotopic xenograft models. RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were performed to study the mechanisms underlying the oncogenic role of YTHDF2.ResultsYTHDF2 expression was positively associated with a higher malignant grade and molecular subtype of glioma and poorer prognosis. YTHDF2 promoted the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, YTHDF2 accelerated UBXN1 mRNA degradation via METTL3-mediated m6A, which, in turn, promoted NF-κB activation. We further revealed that UBXN1 overexpression attenuated the oncogenic effect of YTHDF2 overexpression and was associated with better survival in patients with elevated YTHDF2 expression.ConclusionsOur findings confirmed that YTHDF2 promotes the malignant progression of gliomas and revealed important insight into the upstream regulatory mechanism of NF-κB activation via UBXN1 with a primary focus on m6A modification.

Comprehensive Analysis of the Clinical and Biological Significances of Endoplasmic Reticulum Stress in Diffuse Gliomas.

BackgroundAs a critical organelle for protein and lipid synthesis, the dysfunction of endoplasmic reticulum has a significant impact on multiple biological processes of cells. Thus, in this study, we constructed an ER stress-related risk signature to investigate the functional roles of ER stress in gliomas.MethodsA total of 626 samples from TCGA RNA-seq dataset (training cohort) and 310 samples from CGGA RNA-seq dataset (validation cohort) were enrolled in this study. Clinical information and genomic profiles were also obtained. The ER stress signature was developed by the LASSO regression model. The prognostic value of the risk signature was evaluated by Cox regression, Kaplan-Meier and ROC Curve analyses. Bioinformatics analysis and experiment in vitro were performed to explore the biological implication of this signature.ResultsWe found that the ER stress-related signature was tightly associated with major clinicopathological features and genomic alterations of gliomas. Kaplan-Meier curve and Cox regression analysis indicated that ER stress activation was an independent prognostic factor for patients with glioma. Besides, we also constructed an individualized prognosis prediction model through Nomogram and ROC Curve analysis. Bioinformatics analysis suggested that ER stress activation also promoted the malignant progression of glioma and participated in the regulation of tumor immune microenvironment, especially the infiltration of macrophages in M2 phase. These results were further validated in IHC analysis and cell biology experiments.ConclusionThe ER stress activation had a high prognostic value and could serve as a promising target for developing individualized treatment of glioma.

MiR-433-3p restrains the proliferation, migration and invasion of glioma cells via targeting SMC4

ObjectiveGlioma is a common primary malignant brain tumor characterized by high mortality and poor prognosis. The purpose of this study is to explore the molecular mechanism underlying glioma, aiming to provide a new target for the treatment of glioma to improve the prognosis of patients. MethodsThe differentially expressed genes and regulatory axis affecting the prognosis of glioma were identified with bioinformatics analysis, and the expression of miR-433-3p and SMC4 mRNA was detected with qRT-PCR. The expression of SMC4 and epithelial-mesenchymal transition (EMT)-associated proteins were detected with western blot. The targeting relationship between miR-433-3p and SMC4 was verified with dual-luciferase reporter gene assay. The proliferative ability of glioma cells was detected with CCK-8 assay, while the migration and invasion of glioma cells were detected with Transwell assay. ResultsWe found that the expression of SMC4 was significantly up-regulated in glioma, showing that SMC4 was an unfavorable factor for prognosis and could promote the progression of cancer cells. Its upstream regulator miR-433-3p was significantly down-regulated in glioma, which inhibited the development of cancer cells. Moreover, miR-433-3p could target to inhibit the expression of SMC4. Rescue assay showed that miR-433-3p could affect the development of glioma by regulating the expression of SMC4. ConclusionOur data demonstrate for the first time that SMC4 is a direct target of miR-433-3p, and elucidate the molecular mechanism by which miR-433-3p inhibits the malignant progression of glioma by targeting and down-regulating the expression of SMC4.

Radiation-induced YAP activation confers glioma radioresistance via promoting FGF2 transcription and DNA damage repair

Although radiotherapy is a well-known effective non-surgical treatment for malignant gliomas, the therapeutic efficacy is severely limited due to the radioresistance of tumor cells. Previously, we demonstrated that Yes-associated protein (YAP) promotes glioma malignant progression. However, whether YAP plays a role in radioresistance and its potential value in cancer treatment are still unclear. In this study, we found that high YAP expression is associated with poor prognosis in malignant glioma patients undergoing radiotherapy. Research in immortalized cell lines and primary cells from GBM patients revealed that YAP exhibited a radioresistant effect on gliomas via promoting DNA damage repair. Mechanistically, after radiation, YAP was translocated into the nucleus, where it promoted the expression and secretion of FGF2, leading to MAPK–ERK pathway activation. FGF2 is a novel target gene of YAP. Inhibition of YAP–FGF2–MAPK signaling sensitizes gliomas to radiotherapy and prolongs the survival of intracranial cell-derived and patient-derived xenograft models. These results suggest that YAP–FGF2–MAPK is a key mechanism of radioresistance and is an actionable target for improving radiotherapy efficacy.

MiR-218-5p inhibits the malignant progression of glioma via targeting TCF12.

Several studies have shown the ability of transcription factor 12 (TCF12) to promote tumor malignant progression, but its function in glioma cells has not been fully elucidated. In this study, we analyzed the data from TCGA by bioinformatics and found that in glioma tissue, TCF12 was conspicuously highly expressed while miR-218-5p was significantly low-expressed. The downregulation of miR-218-5p was correlated with adverse prognosis in patients with glioma. miR-218-5p was found to be negatively associated with TCF12 by Pearson correlation analysis, and dual luciferase assay was employed to verify that miR-218-5p and TCF12 had a targeting relationship. qRT-PCR and Western blot assays were used to verify that the expression of TCF12 was regulated by its upstream regulator miR-218-5p. Moreover, cell experiments validated that overexpressed TCF12 could promote the proliferation, migration, and invasion of glioma cells and inhibit their apoptosis, whereas overexpressing miR-218-5p at the same time could reverse this phenomenon. Our study demonstrates the regulatory mechanism of the miR-218-5p/TCF12 axis in gliomas, which lays a foundation for searching for new therapeutic approaches for glioma.

ITPRIP promotes glioma progression by linking MYL9 to DAPK1 inhibition

Epigenetic gene silencing of the tumor suppressor death-associated protein kinase 1 (DAPK1) is implicated in the progression of malignant gliomas. However, the mechanism underlying the repression of DAPK1 in gliomas remains elusive. In this study, we identified the existence of DAPK1-inositol 1,4,5-trisphosphate receptor (IP3R)-interacting protein (ITPRIP) -myosin regulatory light polypeptide 9 (MYL9) complex in malignant glioma cells. Lentivirus co-infection and coimmunoprecipitation showed that ITPRIP bound with the death domain (DD) of DAPK1 in vitro. Further, dissociating ITPRIP-DAPK1 interaction inhibited glioma tumor growth in vitro but not in vivo. Moreover, knockdown of ITPRIP or DAPK1 impaired the ternary complex formation, whereas MYL9 knockdown did not affect ITPRIP-DAPK1 association. We further found that ITPRIP recruited MYL9 to the kinase domain (KD) of DAPK1, and in turn impeded the phosphorylation of MYL9. Accordingly, interference of ITPRIP enhanced the suppressive effects of DAPK1-KD on glioma progression both in vitro and in vivo. Our results demonstrate that ITPRIP plays a crucial role in the inhibition of DAPK1 and enhancement of tumorigenic properties of malignant glioma cells.

The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas

BackgroundFenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood.MethodsIn this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion.ResultsFor the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited.ConclusionsOur results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

Circ-EGFR Functions as an Inhibitory Factor in the Malignant Progression of Glioma by Regulating the miR-183-5p/TUSC2 Axis.

Circular RNAs (circRNAs) have pivotal functions in regulating diverse biological processes of human tumors, including glioma. Herein, a novel circRNA epidermal growth factor receptor (circ-EGFR, hsa_circ_0080223) was researched in glioma. The molecular expression levels were analyzed via quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) and colony formation assays were conducted to assess cell proliferation. Apoptosis was analyzed using flow cytometry. Cell migration and invasion were examined via transwell assay. Interaction relations between targets were verified using dual-luciferase reporter assay. Tumor Suppressor Candidate 2 (TUSC2) protein expression was examined by Western blot. In vivo experiment was performed by establishing xenograft model in mice. The qRT-PCR showed the downregulation of circ-EGFR and TUSC2 but the upregulation of microRNA-183-5p (miR-183-5p) in glioma samples. In vitro assays revealed that circ-EGFR overexpression induced the repression of cell proliferation, migration, and invasion but the promotion of apoptosis. Circ-EGFR was identified as a sponge of miR-183-5p and circ-EGFR-mediated glioma progression inhibition was abolished by miR-183-5p downregulation. Additionally, miR-183-5p targeted TUSC2 and miR-183-5p inhibitor impeded the development of glioma by upregulating the expression of TUSC2. Furthermore, circ-EGFR could regulate the TUSC2 level by sponging miR-183-5p. Glioma growth in vivo was also reduced by circ-EGFR via targeting the miR-183-5p/TUSC2 axis. Altogether, our results suggested that circ-EGFR inhibited the malignant progression of glioma by regulating the levels of miR-183-5p and TUSC2. Circ-EGFR may be a useful therapeutic target to antagonize the glioma progression.

METTL3 enhances the stability of MALAT1 with the assistance of HuR via m6A modification and activates NF-κB to promote the malignant progression of IDH-wildtype glioma.

Understanding the role of N6-methyladenosine (m6A) in tumorigenesis and stem cell maintenance is an emerging field in glioma research. However, it is necessary to study the function of m6A in IDH-mutation and IDH-wildtype gliomas separately. Here, we aimed to elucidate the role and mechanism of the m6A writer METTL3 in regulating the malignant progression of IDH-wildtype gliomas. We demonstrated that METTL3 expression is positively associated with a higher malignant grade and poorer prognosis of IDH-wildtype gliomas but not IDH-mutant gliomas. METTL3 could also promote the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, METTL3 upregulated MALAT1 expression by enhancing its stability via m6A modification. We further revealed that HuR was essential for METTL3-mediated MALAT1 stabilization, and upregulated MALAT1 subsequently activated NF-κB. Taken together, our findings confirmed that METTL3 promoted the malignant progression of IDH-wildtype gliomas and revealed important insight into the upstream regulatory mechanism of MALAT1 and NF-κB with a primary focus on m6A modification.

A Novel Immune-Related Prognostic Biomarker and Target Associated With Malignant Progression of Glioma.

BackgroundGlioma is one of the most common malignancies in the central nervous system and has limited effective therapeutic options. Therefore, we sought to identify a suitable target for immunotherapy.Materials and MethodsWe screened prognostic genes for glioma in the CGGA database and GSE43378 dataset using survival analysis, receiver operating characteristic (ROC) curves, independent prognostic analysis, and clinical correlation analysis. The results were intersected with immune genes from the ImmPort database through Venn diagrams to obtain likely target genes. The target genes were validated as prognostically relevant immune genes for glioma using survival, ROC curve, independent prognostic, and clinical correlation analyses in samples from the CGGA database and GSE43378 dataset, respectively. We also constructed a nomogram using statistically significant glioma prognostic factors in the CGGA samples and verified their sensitivity and specificity with ROC curves. The functions, pathways, and co-expression-related genes for the glioma target genes were assessed using PPI networks, enrichment analysis, and correlation analysis. The correlation between target gene expression and immune cell infiltration in glioma and the relationship with the survival of glioma patients were investigated using the TIMER database. Finally, target gene expression in normal brain, low-grade glioma, and high-grade glioma tissues was detected using immunohistochemical staining.ResultsWe identified TNFRSF12A as the target gene. Satisfactory results from survival, ROC curve, independent prognosis, and clinical correlation analyses in the CGGA and GSE43378 samples verified that TNFRSF12A was significantly associated with the prognosis of glioma patients. A nomogram was constructed using glioma prognostic correlates, including TNFRSF12A expression, primary-recurrent-secondary (PRS) type, grade, age, chemotherapy, IDH mutation, and 1p19q co-deletion in CGGA samples with an AUC value of 0.860, which illustrated the accuracy of the prognosis prediction. The results of the TIMER analysis validated the significant correlation of TNFRSF12A with immune cell infiltration and glioma survival. The immunohistochemical staining results verified the progressive up-regulation of TNFRSF12A expression in normal brain, low-grade glioma, and high-grade glioma tissues.ConclusionWe concluded that TNFRSF12A was a viable prognostic biomarker and a potential immunotherapeutic target for glioma.

CircWEE1/miR-138 axis promotes the malignant progression of glioma by regulating SIRT1.

BackgroundThis study aims to reveal the potential impact of circWEE1 on the malignant progression of gliomas and its mechanism.MethodsReal-time quantitative polymerase chain reaction (qRT-PCR) were used to detect circWEE1 levels in glioma tissues and cell lines. The relationship between circWEE1 expression and glioma metastasis was analyzed.ResultsAfter knocking out or over-expressing circWEE1, the effects on glioma cells were examined separately. Subsequently, the regulatory relationship of circWEE1 to miR-138 was detected by a dual luciferase reporter gene. In addition, we evaluated the role of silent information regulator 1 (SIRT1) in the progression of gliomas affected by circWEE1 through a rescue experiment. CircWEE1 was significantly up-regulated in glioma tissues and cell lines. At the same time, its expression level was significantly higher in glioma patients with lymphatic or distant metastasis than in glioma patients with non-metastasis. The down-regulation of circWEE1 reduced the viability, migration, and invasion ability of T98-G cells. The expression of miR-138 is negatively regulated by WEE1, while miR-138 directly targets and regulates the expression of SIRT1.ConclusionsThe rescue experiment confirmed that SIRT1 is a regulator of circWEE1 in the malignant progression of glioma. In summary, the CircWEE1/miR-138 axis may regulate SIRT1 to promote malignant progression in glioma.

P4HA1 Down-Regulation Inhibits Glioma Invasiveness by Promoting M1 Microglia Polarization.

BackgroundPolarization of microglia cells in the glioma microenvironment is closely related to the malignant progression and invasion of gliomas. Prolyl 4-hydroxylase subunit α1 (P4HA1) is the rate-limiting subunit of prolyl 4-hydroxylase (P4H). In previous studies, we showed that P4HA1 could promote the proliferation, migration, and invasion of glioma cells, but the specific mechanisms through which this occurs have not been fully elucidated.Materials and MethodsInteractions between glioma and microglia cells were analyzed using bioinformatics. Then, co-culture models were used to obtain conditioned media. To characterize microglial cell polarization, we used PCR and immunofluorescence. Proliferation and invasion assays were used to explore the biological behavior of glioma cells affected by microglia. Finally, marker expression was detected using immunohistochemistry in glioblastoma multiform (GBM) specimens.ResultsKnockdown of P4HA1 resulted in reduced chemotaxis of microglia toward GBM cells and increased polarization of microglia toward the M1 phenotype. The changed microglial polarization state, in turn, inhibited the proliferation and invasion of GBM cells. Moreover, in GBM tissue specimens, the P4HA1 expression level is negatively correlated with that of the CD86 microglia M1-specific marker.ConclusionOur results show that P4HA1 promotes immunosuppressive microenvironment formation by cross-talk between GBM and microglia cells and indirectly increases the aggressiveness of GBM.

Circ-UBAP2 functions as sponges of miR-1205 and miR-382 to promote glioma progression by modulating STC1 expression.

BackgroundCircular RNAs (circRNAs) exert vital functions in glioma pathogenesis. CircRNA ubiquitin‐associated protein 2 (circ‐UBAP2, hsa_circ_0008344) has been illuminated as a tumor driver in glioma. Nevertheless, the mechanisms underlying the oncogenic regulation of circ‐UBAP2 in glioma are still undefined.MethodsCirc‐UBAP2, miR‐1205, miR‐382, and GPRC5A were quantified using qRT‐PCR and western blot. Cell viability was detected using a CCK‐8 assay. Cell migration and invasion were measured using the would‐healing and transwell assays. Flow cytometry and colony formation assay were applied to evaluate cell apoptosis and colony formation, respectively. The xenograft model assays were used to examine the impact of circ‐UBAP2 on tumorigenic effect in vivo. Direct relationships among circ‐UBAP2, miR‐1205, miR‐382, and GPRC5A were confirmed using dual‐luciferase reporter assays.ResultsCirc‐UBAP2 expression was upregulated in glioma. The reduced level of circ‐UBAP2 hampered cell proliferation, migration, invasion, and enhanced apoptosis in vitro and weakened tumor growth in vivo. Mechanistically, circ‐UBAP2 directly bound to miR‐1205 and miR‐382. miR‐1205 and miR‐382 mediated the regulation of circ‐UBAP2 silencing on glioma cell behaviors. Moreover, GPRC5A was a functional target of miR‐1205 and miR‐382 in regulating glioma cell behaviors. Furthermore, circ‐UBAP2 mediated GPRC5A expression through miR‐1205 or miR‐382 in glioma cells.ConclusionOur current findings identified that circ‐UBAP2 silencing impeded glioma malignant progression partially by downregulating GPRC5A through targeting miR‐1205 and miR‐382.

LINC00887 aggravates the malignant progression of glioma via upregulating CCND1.

This study aims to explore the impact of LINC00887 on the malignant progression of glioma via upregulating CCND1. LINC00887 and CCND1 levels in glioma patients in different tumor grades or metastasis statuses were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Kaplan-Meier curves were depicted for analyzing the prognostic potential of LINC00887 in glioma patients. Meanwhile, Pearson correlation test was conducted to assess the expression correlation between LINC00887 and CCND1 in glioma tissues. After knockdown of LINC00887 in LN229 and U251 cells, proliferative abilities were examined by cell counting kit-8 (CCK-8) and 5-Ethynyl-2'- deoxyuridine (EdU) assays. Subcellular distribution of LINC00887 was determined. Thereafter, RNA Binding Protein Immunoprecipitation (RIP) was performed to uncover the interaction between LINC00887 and CCND1. After α-amanitin induction in glioma cells overexpressing LINC00887, RNA degradation of CCND1 was examined at 0, 6, 12 and 24 h, respectively. Finally, the synergistic regulation of both LINC00887 and CCND1 on glioma proliferation was explored by CCK-8 assay. It was found that LINC00887 was upregulated in glioma tissues, especially in stage III+IV or metastatic glioma cases. Overall survival was remarkably worse in glioma patients expressing a high level of LINC00887 than those with a low level. CCND1 was upregulated in glioma tissues as well, showing a positive correlation to LINC00887. In addition, LINC00887 was mainly distributed in the cytoplasm and interacted with CCND1, and it shortened the half-life of CCND1. Moreover, the knockdown of LINC00887 inhibited glioma cell proliferation, and this inhibitory effect was abolished by overexpression of CCND1. LINC00887 is upregulated in glioma tissues, and it aggravates the malignant progression of glioma by upregulating CCND1.

Enrichment of branched chain amino acid transaminase 1 correlates with multiple biological processes and contributes to poor survival of IDH1 wild-type gliomas.

Previous studies have reported the association between branched-chain amino acid trasaminase1 (BCAT1) and IDH1 wild-type gliomas. Nonetheless, as a promising target for treatment of primary glioblastoma, comprehensive reports on BCAT1 in gliomas are still lacking. In the present study, we accessed glioma patient cohorts and tissue microarray to evaluate the expression pattern of BCAT1 for determining its prognostic value and its relationship with IDH1 mutation status. Furthermore, we explored the potential regulatory mechanism of BCAT1 in gliomas by comparing the BCAT1 mRNA expression pattern with selected tumor biological signatures. The results showed that BCAT1 is highly expressed in GBM versus lower grade gliomas and could represent the poor survival of IDH1 wild-type gliomas. Moreover, BCAT1 is an independent prognostic factor for glioma patients, high BCAT1 expression is related to unfavorable clinical parameters including older age, IDH wildtype, no 1p/19q codeletion, ATRX wildtype and MGMT unmethylated. Additionally, BCAT1 correlated with apoptosis, hypoxia and angiogenesis processes in gliomas and high expression of BCAT1 revealed higher glycolysis level and increased immunosuppressive status in tumor progression. We concluded that BCAT1 is a strong prognostic factor for glioma patients and involved in the malignant progression of IDH1 wild-type gliomas.

Oncogenic ZEB2/miR-637/HMGA1 signaling axis targeting vimentin promotes the malignant phenotype of glioma

Glioma is the most common primary tumor of the central nervous system. We previously confirmed that zinc finger E-box binding homeobox (ZEB) 2 promotes the malignant progression of glioma, while microRNA-637 (miR-637) is associated with favorable prognosis in glioma. This study aimed to investigate the potential interaction between ZEB2 and miR-637 and its downstream signaling pathway in glioma. The results revealed that ZEB2 could directly bind to the E-box elements in the miR-637 promoter and promote cell proliferation, migration, and invasion via miR-637 downregulation. Subsequent screening confirmed that HMGA1 was a direct target of miR-637, while miR-637 could drive the malignant phenotype of glioma by suppressing HMGA1 both in vitro and in vivo. Furthermore, interaction between cytoplasmic HMGA1 and vimentin was observed, and vimentin inhibition could abolish increased migration and invasion induced by HMGA1 overexpression. Both HMGA1 and vimentin were associated with an unfavorable prognosis in glioma. Additionally, upregulated HMGA1 and vimentin were found in isocitrate dehydrogenase (IDH) wild-type and 1p/19q non-codeletion diffusely infiltrating glioma. In conclusion, we identified an oncogenic ZEB2/miR-637/HMGA1 signaling axis targeting vimentin that promotes both migration and invasion in glioma.