Malignant Phenotype Of Glioma Research Articles

Cysteine and glycine-rich protein 2 is crucial for maintaining the malignant phenotypes of gliomas through its action on Notch signalling cascade

Cysteine and glycine-rich protein 2 (CSRP2) is expressed differently in numerous cancers and plays a key role in carcinogenesis. However, the role of CSRP2 in glioma is unknown. This study sought to determine the expression profile and clinical significance of CSRP2 in glioma and explore its biological functions and mechanisms via lentivirus-mediated CSRP2 silencing experiments. Increased CSRP2 was frequently observed in gliomas, which was associated with clinicopathological characteristics and an unfavourable prognosis. Decreasing CSRP2 led to the suppression of malignant proliferation, metastasis and stemness in glioma cells while causing hypersensitivity to chemotherapeutic drugs. Mechanistic investigations revealed that CSRP2 plays a role in mediating the Notch signalling cascade. Silencing CSRP2 decreased the levels of Notch1, cleaved Notch1, HES1 and HEY1, suppressing the Notch signalling cascade. Reactivation of Notch markedly diminished the tumour-inhibiting effects of CSRP2 silencing on the malignant phenotypes of glioma cells. Notably, CSRP2-silencing glioma cells exhibited reduced potential in the formation of xenografts in nude mice in vivo, which was associated with an impaired Notch signalling cascade. These results showed that CSRP2 is overexpressed in glioma and has a crucial role in sustaining the malignant phenotypes of glioma, suggesting that targeting CSRP2 could be a promising strategy for glioma treatment.

Gelsolin knockdown confers radiosensitivity to glioblastoma cells.

Radiotherapy (RT) is a cornerstone of the glioblastoma (GBM) treatment. However, the resistance of tumour cells to radiation results in early recurrence. The mechanisms underlying GBM radioresistance remain unclear. Screening for differentially expressed genes (DEGs) related to radiation might be a potential solution to this problem. RT-associated DEGs were screened based on the RNA sequencing of 15 paired primary and recurrent GBMs. The mRNA and protein expression of candidate genes were validated in RNA sequencing of The Chinese Genome Atlas (CGGA) dataset and 18 cases of GBM samples. The relationship between the candidate gene and radiation was confirmed in irradiated GBM cells. The association of candidate gene with clinical characteristics and survival was investigated in the CGGA and TCGA dataset. Biological function and pathway analysis were explored by gene ontology analysis. The association of the candidate gene with radiosensitivity was verified using cell counting Kit-8, comet, and colony formation assays invitro and subcutaneous tumour xenograft experiments invivo. Gelsolin (GSN) was selected for further study. GSN expression was significant elevated in recurrent GBM and up-regulated in irradiated GBM cell lines. High expression of GSN was enriched in malignant phenotype of glioma. Moreover, high expression of GSN was associated with poor prognosis. Further investigation demonstrated that GSN-knockdown (GSN-KD) combined with RT significantly inhibited cell proliferation and enhanced radiosensitivity invivo and invitro. Mechanistically, GSN-KD could lead to more serious DNA damage and promotes apoptosis after RT. Radiation induced up-regulated of GSN. GSN-KD could enhance the radiosensitivity of GBM.

Glioma hexokinase 3 positively correlates with malignancy and macrophage infiltration.

Glioma is the main subtype of primary central nervous system (CNS) tumor with high malignancy and poor prognosis under current therapeutic approaches. Glycolysis and suppressive tumor microenvironment (TME) are key markers of glioma with great importance for aggressive features of glioma and inferior clinical outcomes. Hexokinase 3 (HK3) is an important rate-limiting enzyme in glycolysis, but its function in glioma remains unknown. This study comprehensively assessed the expression distribution and immunological effect of HK3 via pan-cancer analysis based on datasets from Genotype Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and The Cancer Genome Atlas (TCGA). Furthermore, it explored the malignant phenotype and genomic landscape between low-HK3 and high-HK3 expression groups in gliomas from Chinese Glioma Genome Atlas (CGGA) and TCGA. Moreover, data from the TIMER website predicted the relationship between macrophage infiltration and HK3 expression. Also, single-cell sequencing data were used to validate the relationship. For pan-cancer patients, HK3 was expressed in various cancers. The results showed that HK3 was highly expressed in gliomas and positively correlated with tumor-infiltrating immune cells (TIICs), immune checkpoints, immunomodulators, and chemokines. Meanwhile, HK3 expression was highest in normal immune cells and tissues. In gliomas, the expression of HK3 was found to be closely correlated with the malignant clinical characteristics and the infiltration of macrophages. Also, HK3 was proven to be positively associated with macrophage through single-cell sequencing data and immunohistochemistry techniques. Finally, it is predicted that samples with high HK3 expression are often malignant entities and also significant genomic aberrations of driver oncogenes. This is the first comprehensive research to figure out the relationship between HK3 and TME characteristics in gliomas. HK3 is positively associated with macrophage infiltration and can induce the immunosuppressive TME and malignant phenotype of gliomas.

BPTF promotes glioma development through USP34-mediated de-ubiquitination of FOXC1.

Glioma is the most prevalent malignant tumor of the brain, and the study of the molecular mechanisms associated with its development has important clinical significance. Our previous study found that BPTF promotes the malignant phenotype of glioma and is significantly associated with poor prognosis; the downstream regulatory mechanisms are explored in this study. Western blot and immunohistochemical staining were used to detect protein expression in cells or tissues. BPTF knockdown as well as FOXC1-overexpressing lentiviruses were used in combination for the construction of the U251 cell model, leading to functional rescue experiments. CCK8 assay, flow cytometry, scratch assay, and Transwell assay were used to detect cell proliferation, apoptosis, and migration, respectively. Finally, immunoprecipitation assays, combined with western blot (WB), were used to detect the interaction between proteins as well as the level of ubiquitination modification. The obtained results suggested that BPTF knockdown may inhibit the malignant behavior of glioma cells by downregulating FOXC1 expression. Moreover, FOXC1 expression was significantly higher in glioma tissues than in normal brain tissues and was significantly associated with higher tumor stage and worse patient prognosis. Finally, the mechanism of FOXC1 regulation by BPTF was found to result from the affected protein stability of FOXC1 through USP34-mediated de-ubiquitylation. In conclusion, the BPTF/FOXC1 axis was identified as a key promotor in glioma development and may be a potential target in the inhibition of glioma development.

An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype.

Extensive infiltration by tumor-associated macrophages (TAM) in combination with myeloid-derived suppressor cells constitute the immunosuppressive microenvironment and promote the malignant phenotype of gliomas. The aggressive mesenchymal (MES)-subtype glioma stem cells (GSC) are prominent in the immunosuppressive microenvironment of gliomas. However, the underlying immune-suppressive mechanisms are still unknown. The current study showed that the antitumor immune microenvironment was activated in glioma in Nfat1-/- mice, suggesting induction of the immune-suppressive microenvironment by nuclear factor of activated T cells-1 (NFAT1). In TAMs, NFAT1 could upregulate the transcriptional activity of complement 3 (C3) and increase the secretion of C3a, which could then bind to C3aR and promote M2-like macrophage polarization by activating TIM-3. Simultaneously, C3a/C3aR activated the Ca2+-NFAT1 pathway, forming a positive feedback loop for the M2-like polarization of TAMs, which further promoted the MES transition of GSCs. Finally, disruption of this feedback loop using a C3aR inhibitor significantly inhibited glioma growth both in vitro and in vivo. The current study demonstrated that a NFAT1-C3a-C3aR positive feedback loop induces M2-like TAMs and further promotes the malignant phenotype of GSCs, which might be the potential therapeutic target for glioma.

TMEM64 aggravates the malignant phenotype of glioma by activating the Wnt/β-catenin signaling pathway

Transmembrane protein 64 (TMEM64), a member of the family of transmembrane protein, is an α-helical membrane protein. Its precise role in various types of tumors, including glioma, is unclear. This study used immunohistochemical (IHC) staining, western blotting, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) techniques to show that TMEM64 expression was significantly higher in glioma cells and tissues compared to normal cells and tissues, respectively. Additionally, a correlation between high TMEM64 expression and higher grade as well as a worse prognosis was found. TMEM64 enhanced cell proliferation and tumorigenicity while inhibiting glioma cell apoptosis in vitro and in vivo, according to loss- and gain-of-function studies. Mechanistically, it was discovered that TMEM64 increased the malignant phenotype of gliomas by accelerating the translocation of β-catenin from the cytoplasm to the nucleus, thereby activating the Wnt/β-catenin signaling pathway. Stimulation with the Wnt/β-catenin signaling pathway activator CHIR-99021 successfully reversed the malignant phenotype of glioma; however, these effects were inhibited upon TMEM64 silencing. Stimulation with the Wnt/β-catenin signaling pathway inhibitor XAV-939 successfully rescued the malignant phenotype of glioma, which was promoted upon TMEM64 overexpression. Our results provide that TMEM64 as a novel prognostic biomarker and a potential treatment target for glioma.

Low expression of GRM4 is associated with poor prognosis and tumor immune infiltration in glioma

Introduction The metabotropic glutamate receptor 4 (mGlu4, GRM4) exhibits significant expression within the central nervous system (CNS) and has been implicated to be correlated with a poor prognosis. Objective This study was aimed to elucidate the relationship between the expression profile of GRM4 and the prognosis of glioma patients. Methods RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and China Glioma Genome Atlas (CGGA) repositories were used to evaluate the potential relationship. The value of clinical prognostic about GRM4 was assessed using clinical survival data from CGGA and TCGA. The GEPIA database was used to select genes like GRM4. PPI network was constructed by the database of (STRING), GO and KEGG analyses were performed. TargetScan, TarBase, miRDB, and starBase were used to explore miRNAs that could regulate GRM4 expression. EWAS Data Hub, MethSurv, and MEXPRESS were used for the analysis and relationship between DNA methylation and GRM4 expression and prognosis in glioma. TIMER2.0 and CAMOIP databases were used to assess the association between immune cell infiltration and GRM4. Human GBM cell lines were used to validate the function of GRM4. Results Our study shows that GRM4 is under expressed among gliomas and accompanied by poorer OS. Multivariate analysis showed that low mRNA expression of GRM4 was an independent factor of prognostic for shorter OS in all glioma patients. MiR-1262 affects the malignant phenotype of gliomas through GRM4. Methylation of DNA plays an important role in the instruction of GRM4 expression, the methylation level of GRM4 in glioma tissue is higher in comparison to normal tissue, and the higher methylation level was accompanied with the worse prognosis. Further analysis showed that GRM4 mRNA expression in GBM linked negatively with common lymphoid progenitor, Macrophage M1, Macrophage, and T cell CD4+ Th2, but not with the tumor purity. Overexpression of GRM4 prevents the migration of human GBM cell lines in vitro. Conclusion GRM4 may have a substantial impact on the infiltration of immune cells and serve as a valuable prognostic biomarker in gliomas.

Molecular Aspects of Cancer-associated Glycans in Gliomas

Mammalian cells express a variety of glycans on their cell surface. The pattern of the expressed glycans is closely regulated by glycosyltransferases, their doners and acceptors, glycosidases and related systems. In pre-disease and disease conditions, it is well known that the pattern of the expression of glycans is altered and unusual glycans are frequently generated, which leads to the disruption in glycan homeostasis. In cancer, the ectopic expression of those unusual glycans has been identified and they are considered to be cancer biomarkers and therapeutic targets. Here, I review the molecular functions of ganglioside GD3 and the heparan sulfate glycosaminoglycan for enhancing the malignant phenotypes of glioma. The expression of these glycans on the cell surface strengthens cell signaling that is transduced through receptor type of tyrosine kinases (RTKs), especially the platelet-derived growth factor receptor α (PDGFRα). A concise discussion regarding the possibility of the development of GD3- or heparan sulfate glycosaminoglycan-targeting therapies for patients suffering from glioma is also included.

TANK shapes an immunosuppressive microenvironment and predicts prognosis and therapeutic response in glioma.

Glioma, the most prevalent malignant intracranial tumor, poses a significant threat to patients due to its high morbidity and mortality rates, but its prognostic indicators remain inaccurate. Although TRAF-associated NF-kB activator (TANK) interacts and cross-regulates with cytokines and microenvironmental immune cells, it is unclear whether TANK plays a role in the immunologically heterogeneous gliomas. TANK mRNA expression patterns in public databases were analyzed, and qPCR and IHC were performed in an in-house cohort to confirm the clinical significance of TANK. Then, we systematically evaluated the relationship between TANK expression and immune characteristics in the glioma microenvironment. Additionally, we evaluated the ability of TANK to predict treatment response in glioma. TANK-associated risk scores were developed by LASSO-Cox regression and machine learning, and their prognostic ability was tested. TANK was specifically overexpressed in glioma and enriched in the malignant phenotype, and its overexpression was related to poor prognosis. The presence of a tumor microenvironment that is immunosuppressive was evident by the negative correlations between TANK expression and immunomodulators, steps in the cancer immunity cycle, and immune checkpoints. Notably, treatment for cancer may be more effective when immunotherapy is combined with anti-TANK therapy. Prognosis could be accurately predicted by the TANK-related risk score. High expression of TANK is associated with the malignant phenotype of glioma, as it shapes an immunosuppressive tumor microenvironment. Additionally, TANK can be used as a predictive biomarker for responses to various treatments and prognosis.

Epithelial-mesenchymal transition is the main way in which glioma-associated microglia/macrophages promote glioma progression.

Microglia/macrophages make up the largest population of tumor-infiltrating cells. Numerous studies have demonstrated that glioma-associated microglia/macrophages (GAMs) could promote the malignant progression of gliomas in various pathways. However, the primary function of GAMs in glioma remains inconclusive. First, by the CIBERSORT algorithm, we evaluated the content of microglia/macrophages in glioma tissues by bioinformatic analysis of omic data from thousands of glioma samples. Subsequently, we analyzed and confirmed the significant relationship between GAMs and the malignant phenotype of glioma, including survival time, IDH mutation status, and time of symptom onset. Afterward, Epithelial-Mesenchymal Transition (EMT) was identified by Gene Set Enrichment Analysis (GSEA) from numerous biological processes as the most relevant mechanism of malignant progression to GAMs. Moreover, a series of clinical samples were detected, including normal brain and various-grade glioma tissues. The results not only showed that GAMs were significantly associated with gliomas and their malignancy but also that GAMs were highly correlated with the degree of EMT in gliomas. In addition, we isolated GAMs from glioma samples and constructed co-culture models (in vitro) to demonstrate the promotion of the EMT process in glioma cells by GAMs. In conclusion, our study clarified that GAMs exert oncogenic effects with EMT in gliomas, suggesting the possibility of GAMs as immunotherapeutic targets.

The FDX1 methylation regulatory mechanism in the malignant phenotype of glioma

To explore FDX1 methylation as a regulatory mechanism in the malignant phenotype of glioma, we screened for pathways involved through bioinformatic analysis, then proceeded with RIP and cell models to verify the regulation of RNAs and mitophagy. We chose Clone and Transwell assays to evaluate the malignant phenotype of glioma cells. MMP was detected by flow cytometry and mitochondrial morphology was observed by TEM. We also constructed animal models to study the sensitivity of glioma cells to cuproptosis. We successfully identified the signalling pathway: our cell model showed that C-MYC could upregulate FDX1 through YTHDF1 and inhibit mitophagy in glioma cells. Functional experiments revealed C-MYC could also enhance glioma cell proliferation and invasion via YTHDF1 and FDX1. In vivo experiments showed glioma cells were highly sensitive to cuproptosis. We concluded that C-MYC could upregulate FDX1 by m6A methylation, thus promoting the malignant phenotype in glioma cells.

Biological implications and clinical potential of invasion and migration related miRNAs in glioma.

Gliomas are the most common primary malignant brain tumors and are highly aggressive. Invasion and migration are the main causes of poor prognosis and treatment resistance in gliomas. As migration and invasion occur, patient survival and prognosis decline dramatically. MicroRNAs (miRNAs) are small, non-coding 21-23 nucleotides involved in regulating the malignant phenotype of gliomas, including migration and invasion. Numerous studies have demonstrated the mechanism and function of some miRNAs in glioma migration and invasion. However, the biological and clinical significance (including diagnosis, prognosis, and targeted therapy) of glioma migration and invasion-related miRNAs have not been systematically discussed. This paper reviews the progress of miRNAs-mediated migration and invasion studies in glioma and discusses the clinical value of migration and invasion-related miRNAs as potential biomarkers or targeted therapies for glioma. In addition, these findings are expected to translate into future directions and challenges for clinical applications. Although many biomarkers and their biological roles in glioma invasion and migration have been identified, none have been specific so far, and further exploration of clinical treatment is still in progress; therefore, we aimed to further identify specific markers that may guide clinical treatment and improve the quality of patient survival.

GDNF regulates lipid metabolism and glioma growth through RET/ERK/HIF‑1/SREBP‑1.

Cancer cells rewire their metabolism to meet the demands of growth and survival and this metabolic reprogramming has been recognized as an emerging hallmark of cancer. However, the respective mechanisms remain elusive and the contribution of aberrant lipid metabolism to the malignant phenotypes of glioma are unclear. The present study demonstrated that glial-derived neurotrophic factor (GDNF) is highly expressed in glioma and associated with poor clinical outcomes. In addition, there was a significant correlation between GDNF/rearranged during transfection (RET)/ERK signaling and sterol regulatory element-binding protein-1 (SREBP-1) expression in glioma cells. Pharmacological or genetic inhibition of GDNF-induced RET/ERK activity downregulated SREBP-1 expression and SREBP-1-mediated transcription of lipogenic genes. Additionally, GDNF regulated SREBP-1 activity by promoting hypoxia-inducible factor-1α (HIF-1α) mediated glucose absorption and hexosamine biosynthetic pathway mediated SREBP cleavage-activating protein N-glycosylation. In addition, the inhibition of SREBP-1 reduced the in vitro GDNF-induced glioma cell proliferation. The results elucidated the complex relationship between GDNF/RET/ERK signaling and dysregulated glycolipid-metabolism, which shows great potential to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

Sevoflurane inhibits the malignant phenotypes of glioma through regulating miR-146b-5p/NFIB axis.

Sevoflurane is a common used inhaled anesthetic that was reported to regulate the progression of multiple cancers. Here, we aimed to investigate the function and regulatory mechanism underlying sevoflurane in glioma cells. A172 and U251 cells were treated with different concentrations of sevoflurane. Colony formation, EdU satining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), flow cytometry, and transwell assays were performed to evaluate cell proliferation, apoptosis, migration and invasion, respectively. Circ_VCAN, microRNA-146b-5p (miR-146b-5p) and nuclear factor I B (NFIB) expression levels were assessed by real-time quantitative PCR (RT-qPCR) or western blot. Bioinformatics analysis and dual-luciferase reporter assay were applied to evaluate the correlation between miR-146b-5p and circ_VCAN or NFIB. A xenograft glioma mice model was established to verify the effect of sevoflurane on tumor growth in vivo. Sevoflurane (Sev) inhibited proliferation, migration, invasion, and elevated apoptosis of A172 and U251 cells. Sevoflurane treatment inhibited the expression of circ_VCAN and NFIB, but elevated the expression of miR-146b-5p in glioma cells. Overexpression of circ_VCAN alleviated the inhibition effects of sevoflurane on the malignant phenotypes of glioma in vitro and in vivo. Besides, miR-146b-5p is a target of circ_VCAN and negatively regulated NFIB expression. Overexpression of miR-146b-5p partly reversed the effects of circ_VCAN in Sev-treated glioma cells. Furthermore, miR-146b-5p deletion enhanced glioma progression in sevoflurane treated glioma cells by targeting NFIB. Moreover, circ_VCAN could upregulate NFIB expression by sponging miR-146b-5p in Sev-treated glioma cells. Sevoflurane alleviated proliferation, migration and invasion, but enhanced apoptosis of glioma cells through regulating circ_VCAN/miR-146b-5p/NFIB axis.

LRRFIP1, an epigenetically regulated gene, is a prognostic biomarker and predicts malignant phenotypes of glioma.

AimsGlioblastoma (GBM) is the most common malignant brain tumor with an adverse prognosis in the central nervous system. Traditional histopathological diagnosis accompanied by subjective deviations cannot accurately reflect tumor characteristics for clinical guidance. DNA methylation plays a critical role in GBM genesis. The focus of this project was to identify an effective methylation point for the classification of gliomas, the interactions between DNA methylation and potential epigenetic targeted therapies for clinical treatments.MethodsThree online (TCGA, CGGA, and REMBRANDT) databases were employed in this study. T‐test, Venn analysis, univariate cox analysis, and Pearson's correlation analysis were adopted to screen significant prognostic methylation genes. Clinical samples were collected to determine the distributions of LRRFIP1 (Leucine Rich Repeat of Flightless‐1 Interacting Protein) protein by immunohistochemistry assay. Kaplan–Meier survival and Cox analysis were adopted to evaluate the prognostic value of LRRFIP1. Nomogram model was used to construct a prediction model. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway were performed to explore functions and related mechanisms of LRRFIP1 in gliomas.ResultsOur results showed that 16 genes were negatively connected with their methylation level and correlated with clinical prognosis of GBM patients. Among them, LRRFIP1 expression showed the highest correlation with its methylation level. LRRFIP1 was highly expressed in WHO IV, mesenchymal, and IDH wild‐type subtype. LRRFIP1 expression was an independent risk factor for OS (overall survival) in gliomas.Conclusion LRRFIP1 is an epigenetically regulated gene and a potential prognostic biomarker for glioma. Our research may be beneficial to evaluate clinical efficacy, assess the prognosis, and provide individualized treatment for gliomas.

GDF15 expression in glioma is associated with malignant progression, immune microenvironment, and serves as a prognostic factor.

AimsGrowth differentiation factor 15 (GDF15) is involved in lots of crucial inflammatory and immune response. The clinical and immune features for GDF15 in glioma have not been specifically investigated so far.MethodsGene expression profiles obtained from public glioma datasets were used to explore the biological function of GDF15 and its impact on immune microenvironment. Interference with GDF15 in several glioma cell lines to verify its functions in vitro. Survival data were used for the survival analysis and establishment of a nomogram predictive model.ResultsGDF15 was up‐regulated in various malignant phenotypes of glioma. Function analysis and in vitro experiments revealed that GDF15 was associated with malignant progression and NF‐κB pathway. GDF15 was closely correlated to inflammatory response, infiltrating immune cells, and immune checkpoint molecules, especially in lower grade glioma (LGG). High expression level of GDF15 predicted poor survival in LGG, while the effect on glioblastoma (GBM) was not significant. A nomogram predictive model combining GDF15 and other prognostic factors was constructed and showed ideal predictive performance.ConclusionsGDF15 could serve as an interesting prognostic biomarker for LGG. Regulating the expression of GDF15 may help solve the dilemma of immunotherapy in glioma.

MicroRNA‑218 inhibits the malignant phenotypes of glioma by modulating the TNC/AKT/AP‑1/TGFβ1 feedback signaling loop.

Gliomas are the most malignant and common tumors of the human brain, and the prognosis of glioma patients is extremely poor MicroRNAs (miRNAs or miRs) play critical roles in different types of cancer by performing post-transcriptional regulation of gene expression Although miR-218 has been demonstrated to be decreased in gliomas, its role in gliomas remains largely unknown miR-218 expression was analyzed in gliomas and normal brain tissues (control subjects) using a dataset from The Cancer Genome Atlas A series of in vitro and in vivo studies were performed to determine the biological roles of miR-218 in glioma cells Potential targets of miR-218 were identified using a dual-luciferase reporter system Western blot and dual-luciferase reporter system experiments were performed to evaluate the regulatory effect of miR-218 on the tenascin C (TNC)/AKT/activator protein 1 (AP-1)/transforming growth factor β1 (TGFβ1) pathway It was demonstrated that miR-218 was significantly downregulated in gliomas compared with control subjects, and played potent tumor suppressor roles in glioma cells by inhibiting cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice, as well as inducing cell cycle arrest and apoptosis Mechanistically, miR-218 inhibited malignant phenotypes of glioma cells by binding to the 3′-untranslated region of its target TNC and subsequently suppressing its expression As a result, miR-218 could reduce AKT phosphorylation and subsequently inhibit transcriptional activity of AP-1 by reducing JNK phosphorylation, downregulating the expression of TGFβ1, while TGFβ1 was able to, in turn, activate the TNC/AKT/AP-1 signaling axis Our data revealed a previously unknown tumor suppressor role of miR-218 by blocking the TNC/AKT/AP-1/TGFβ1-positive feedback loop in glioma

SIPA1 boosts migration and proliferation, and blocks apoptosis of glioma by activating the phosphorylation of the FAK signaling pathway.

BackgroundWe aimed to analyze the regulatory effects of SIPA1 (signal-induced proliferation-associated protein 1) on glioma progression and the dominant signaling pathway.MethodsDifferential level of SIPA1 in glioma and normal tissues and cells was determined. Migratory, proliferative, apoptotic and cell cycle progression changes in A172 cells with overexpression or knockdown of SIPA1 were examined. Finally, protein levels of phosphorylated FAKs in A172 cells intervened by SIPA1, and the FAK inhibitor PF562271 were detected.ResultsSIPA1 was upregulated in glioma cases. Knock-down of SIPA1 reduced migratory and proliferative rates of glioma cells, increased apoptotic cell rate, and declined cell ratio in the S phase. The knockdown of SIPA1 also downregulated cell cycle proteins. In addition, SIPA1 upregulated phosphorylated FAKs in A172 cells and thus boosted malignant phenotypes of glioma.ConclusionsSIPA1 is upregulated in glioma that boosts migratory and proliferative potentials of glioma cells by activating the phosphorylation of the FAK signaling pathway.

A positive feedback loop of LINC00662 and STAT3 promotes malignant phenotype of glioma

BackgroundLong noncoding RNAs (lncRNAs) have been reported to be associated with tumorigenesis and development of glioma. LINC00662 has been involved in the pathogenesis of various human cancers. However, the mechanism underlying which LINC00662 exerts its role in glioma needs further exploration. In addition, regulation mechanism of LINC00662 expression in glioma remains unknown. Methods and materialsRT-qPCR was performed to evaluate the expression levels of LINC00662, miR-340-5p in glioma tissues and cell lines. The effect of LINC00662 and miR-340-5p in cell proliferation and invasion was assessed by Cell Counting Kit-8(CCK-8), clone colony formation and Transwell assay. Luciferase reporter assays and RNA immunoprecipitation assay validated the miR-340-5p-target relationships with LINC00662 or STAT3. CHIP-qPCR and Luciferase reporter assays were used to demonstrate the interaction between STAT3 and the promoter region of LINC00662. A tumor xenografts model was implemented to verify the effect of LINC00662 on glioma development in vivo. ResultsWe found that LINC00662 was frequently highly expressed and related to the malignant phenotype of glioma. LINC00662 knockdown inhibited the proliferation, invasion and glioma genesis of glioma. LINC00662 acted as a ceRNA sponging miR-340-5p to protect the expression of STAT3. In addition, STAT3 was forced to the promoter region of LINC00662 and promoted its transcription. In vivo experiments demonstrated that targeting LINC00662 may be a potential strategy in glioma therapy. ConclusionThere was a positive regulation loop between LINC00662 and STAT3 in glioma. LINC00662 might be an oncogene in glioma. Targeting LINC00662 was a potential strategy in glioma therapy.

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

BackgroundA large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on tumor biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms.MethodsThe effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., Cell Counting Kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The acyl-biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs.ResultsIn this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling.ConclusionsIn conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.