Malignant Progression Of Glioma Research Articles

The interaction between ASF1B and TLK1 promotes the malignant progression of low-grade glioma

Aim Low-grade glioma (LGG), which is the second most frequent adult brain malignancy, severely threatens patients’ health and has a high recurrence rate. Histone H3/H4 chaperone anti-silencing function 1 B (ASF1B) has a tight association with the initiation and development of tumours. The expression and regulation mechanism of ASF1B in LGG were discussed. Methods ASF1B expression in LGG patients as well as the association of ASF1B with overall survival and disease-free survival of LGG patients were predicted by GEPIA database. The independent prognostic value of ASF1B in LGG patients was investigated by TCGA database. RT-qPCR, together with western blot was applied for the assessment of ASF1B in LGG cell lines. After ASF1B expression was inhibited, CCK8 and colony formation assays judged cell proliferation. Flow cytometry analysis and TUNEL assay appraised cell cycle as well as apoptosis. Cell migratory and invasive capacities were measured by wound healing as well as Transwell assays. Western blot tested the expression of proliferation-, cycle-, apoptosis-, and metastasis-associated proteins. STRING and GeneMANIA database predicted the relationship between ASF1B and tousled-like kinase 1 (TLK1). ChIP assay testified the affinity of ASF1B with TLK1. Subsequently, TLK1 was overexpressed and ASF1B expression interfered, and the functional assays were executed. Results ASF1B was discovered to be increased in LGG tissues and cells and indicates an unfavourable prognosis for LGG patients. ASF1B was not an independent prognostic factor for LGG. ASF1B deficiency obstructed the proliferation, cell cycle as well as metastasis of LGG cells, and induced cell death, which might be realized through the interaction with TLK1. Conclusion The interaction between ASF1B and TLK1 promoted the malignant progression of LGG. Key messages TLK1 interacts with ASF1B. Interference with ASF1B inhibits the proliferative, invasive and migratory capabilities and induces the cycle arrest, along with the apoptosis of LGG cells. The interaction between ASF1B and TLK1 promotes the malignant progression of LGG.

Dynamic Regulation Genes at Microtubule Plus Ends: A Novel Class of Glioma Biomarkers

Glioma is the most prevalent and aggressive primary nervous system tumor with an unfavorable prognosis. Microtubule plus-end-related genes (MPERGs) play critical biological roles in the cell cycle, cell movement, ciliogenesis, and neuronal development by coordinating microtubule assembly and dynamics. This research seeks to systematically explore the oncological characteristics of these genes in microtubule-enriched glioma, focusing on developing a novel MPERG-based prognostic signature to improve the prognosis and provide more treatment options for glioma patients. First, we thoroughly analyzed and identified 45 differentially expressed MPERGs in glioma. Based on these genes, glioma patients were well distinguished into two subgroups with survival and tumor microenvironment infiltration differences. Next, we further screened the independent prognostic genes (CTTNBP2, KIF18A, NAV1, SLAIN2, SRCIN1, TRIO, and TTBK2) using 36 prognostic-related differentially expressed MPERGs to construct a signature with risk stratification and prognostic prediction ability. An increased risk score was related to the malignant progression of glioma. Therefore, we also designed a nomogram model containing clinical factors to facilitate the clinical use of the risk signature. The prediction accuracy of the signature and nomogram model was verified using The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets. Finally, we examined the connection between the signature and tumor microenvironment. The signature positively correlated with tumor microenvironment infiltration, especially immunoinhibitors and the tumor mutation load, and negatively correlated with microsatellite instability and cancer stemness. More importantly, immune checkpoint blockade treatment and drug sensitivity analyses confirmed that this prognostic signature was helpful in anticipating the effect of immunotherapy and chemotherapy. In conclusion, this research is the first study to define and validate an MPERG-based signature closely associated with the tumor microenvironment as a reliable and independent prognostic biomarker to guide personalized choices of immunotherapy and chemotherapy for glioma patients.

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.

Single-cell RNA sequencing reveals immunosuppressive myeloid cell diversity during malignant progression in a murine model of glioma

Recent studies have shown the importance of the dynamic tumor microenvironment (TME) in high-grade gliomas (HGGs). In particular, myeloid cells are known to mediate immunosuppression in glioma; however, it is still unclear if myeloid cells play a role in low-grade glioma (LGG) malignant progression. Here, we investigate the cellular heterogeneity of the TME using single-cell RNA sequencing in a murine glioma model that recapitulates the malignant progression of LGG to HGG. LGGs show increased infiltrating CD4+ and CD8+ Tcells and natural killer (NK) cells in the TME, whereas HGGs abrogate this infiltration. Our study identifies distinct macrophage clusters in the TME that show an immune-activated phenotype in LGG but then evolve to an immunosuppressive state in HGG. We identify CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Targeting these intra-tumoral macrophages in the LGG stage may attenuate their immunosuppressive properties and impair malignant progression.

Hypoxic glioma cell-secreted exosomal circ101491 promotes the progression of glioma by regulating miR-125b-5p/EDN1

Hypoxia and exosomes play important roles in the occurrence and development of glioma. While circRNAs are involved in biological processes of various tumors, the mechanism underlying exosome-dependent regulatory effects of circRNAs on the progression of glioma under hypoxia is unclear. Results suggested that circ101491 was overexpressed in tumor tissues and plasma exosomes of glioma patients, while the overexpression of circ101491 was closely related to the differentiation degree and TNM staging of the patients. Moreover, circ101491 overexpression promoted viability, invasion and migration of glioma cells both in vivo and in vitro; the above regulatory effects can be reversed by inhibition of circ101491 expression. Mechanistic studies revealed that circ101491 upregulated EDN1 expression through sponging miR-125b-5p, thus facilitating glioma progression. In summary, hypoxia could promote circ101491 overexpression in glioma cell-derived exosomes, and circ101491/miR-125b-5p/EDN1 regulatory axis might be implicated in the malignant progression of glioma.

Construction of a pyroptosis-related lncRNAs signature for predicting prognosis and immunotherapy response in glioma.

Recent studies have proved that pyroptosis-related long non-coding RNAs (PRlncRNAs) are closely linked to tumor progression, prognosis, and immunity. Here, we systematically evaluated the correlation of PRlncRNAs with glioma prognosis. This study included 3 glioma cohorts (The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and Gravendeel). Through Pearson correlation analysis, PRlncRNAs were screened from these 3 cohorts. Univariate Cox regression analysis was then carried out to determine the prognostic PRlncRNAs. A pyroptosis-related lncRNAs signature (PRLS) was then built by least absolute shrinkage and selection operator and multivariate Cox analyses. We systematically evaluated the correlation of the PRLS with the prognosis, immune features, and tumor mutation burden in glioma. A total of 14 prognostic PRlncRNAs overlapped in all cohorts and were selected as candidate lncRNAs. Based on The Cancer Genome Atlas cohort, a PRLS containing 7 PRlncRNAs was built. In all cohorts, the PRLS was proved to be a good predictor of glioma prognosis, with a higher risk score related to a poorer prognosis. We observed obvious differences in the immune microenvironment, immune cell infiltration level, and immune checkpoint expression in low- and high-risk subgroups. Compared with low-risk cases, high-risk cases had lower Tumor Immune Dysfunction and Exclusion scores and greater tumor mutation burden, indicating that high-risk cases can be more sensitive to immunotherapy. A nomogram combining PRLS and clinical parameters was constructed, which showed more robust and accurate predictive power. In conclusion, the PRLS is a potentially useful indicator for predicting prognosis and response to immunotherapy in glioma. Our findings may provide a useful insight into clinically individualized treatment strategies for patients.

Marsdenia tenacissima extract prevents the malignant progression of glioma through upregulating lncRNA MEG3 and SFRP1-dependent inhibition of Wnt/β-catenin pathway.

Recent studies have highlighted the tumor-suppressive effect of Marsdenia tenacissima extract (MTE) on human cancers. This research unveils the potential impact of MTE on glioma and ascertains the relevant molecular mechanisms. Glioma cells were treated with MTE, with normal human astrocytes (NHAs) as controls. A battery of function experiments, including the CCK-8 viability test, colony formation assay, scratch migration assay, and Transwell invasion assay, was executed to address the responses of glioma cells to MTE treatment and gain or loss of function of lncMEG3, miR-542-3p, and SFRP1. FISH, RIP, and dual-luciferase reporter assays were adopted for assessing gene interactions. U251-GFP-Luc cells were delivered into nude mice through intracranial injection to develop an orthotopic glioma model for in vivo validation. 200 mg/mL MTE could suppress the proliferating, migrating, and invading properties of glioma cells but not affect those of NHAs. MTE treatment enhanced the expression of lncMEG3, which competes with SFRP1 for binding miR-542-3p. SFRP1 could inactivate the Wnt/β-catenin pathway. Animal experimentation substantiated the antitumor activity and mechanism of MTE in nude mice. MTE suppresses glioma via the lncMEG3/miR-542-3p/SFRP1/Wnt/β-catenin axis. These findings contribute to a theoretical basis for the use of MTE for glioma patients.

Study on the role and mechanism of HAX-1 and S100A12 in promoting malignant progression of glioma

Study on the role and mechanism of HAX-1 and S100A12 in promoting malignant progression of glioma

The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway

Glioma is the most aggressive and common malignant neoplasms in human brain tumors. Numerous studies have showed that glioma stem cells (GSCs)drive the malignant progression of gliomas. Recent studies have revealed that circRNAs can maintain stemness and promote malignant progression of glioma stem cells. We used bioinformatics analysis to identify circRNAs and potential RNA-binding proteins (RBPs) in glioma. qRT-PCR, western blotting, RNA FISH, RNA pull-down, RNA immunoprecipitation assay, ChIP, immunohistochemistry, and immunofluorescence methods were used to quantified the expression of circNCAPG, U2AF65, RREB1 and TGF-β1, and the underlying mechanisms between them. MTS, EDU, neurosphere formation, limiting dilution neurosphere formation and transwell assays examined the proliferation and invasive capability of GSCs, respectively. We identified a novel circRNA named circNCAPG was overexpressed and indicated the poor prognosis in glioma patients. Upregulating circNCAPG promoted the malignant progression of GSCs. RNA binding protein U2AF65 could stabilize circNCAPG by direct binding. Mechanically, circNCAPG interacted with and stabilized RREB1, as well as stimulated RREB1 nuclear translocation to activate TGF-β1 signaling pathway. Furthermore, RREB1 transcriptionally upregulated U2AF65 expression to improve the stability of circNCAPG in GSCs, which established a feedback loop involving U2AF65, circNCAPG and RREB1. Since circRNA is more stable than mRNA and can execute its function continuously, targeting circNCAPG in glioma may be a novel promising therapeutic.

Emerging Perspectives on the Antiparasitic Mebendazole as a Repurposed Drug for the Treatment of Brain Cancers.

Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. The use of drugs in ways other than their original FDA-approved indications could offer novel avenues such as bypassing the chemoresistance and recurrence seen with conventional therapy and treatment; moreover, it can offer a safe and economic strategy for combination therapy. Recent works have demonstrated the anticancer properties of the FDA-approved drug Mebendazole. This synthetic benzimidazole proved effective against a broad spectrum of intestinal Helminthiasis. Mebendazole can penetrate the blood-brain barrier and has 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. Moreover, several preclinical models and ongoing clinical trials explore the efficacy of Mebendazole in multiple cancers, including acute myeloid leukemia, brain cancer, oropharyngeal squamous cell carcinoma, breast cancer, gastrointestinal cancer, lung carcinoma, adrenocortical carcinoma, prostate cancer, and head and neck cancer. The present review summarizes central literature regarding the anticancer effects of MBZ in cancer cell lines, animal tumor models, and clinical trials to suggest possible strategies for safe and economical combinations of anticancer therapies in brain cancer. Mebendazole might be an excellent candidate for the treatment of brain tumors because of its efficacy both when used as monotherapy and in combination as an enhancement to standard chemotherapeutics and radiotherapy, due to its effectiveness on tumor angiogenesis inhibition, cell cycle arrest, apoptosis induction, and targeting of critical pathways involved in cancer such as Hedgehog signaling. Therefore, attention to MBZ repurposing has recently increased because of its potential therapeutic versatility and significant clinical implications, such as reducing medical care costs and optimizing existing therapies. Using new treatments is essential, particularly when current therapeutics for patients with brain cancer fail.

MiR-484 promotes the malignant progression of glioma by inhibiting CDKN2A expression.

Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) is involved in glioma progression, but the specific molecular mechanism of CDKN2A in glioma cell migration and invasion needs to be further explored. Data related to CDKN2A expression and glioma overall survival were obtained from The Cancer Genome Atlas (TCGA) database. Then, CDKN2A expression in glioma tissues/cells or paracancer tissues/astrocytes was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blot. Afterwards, Wound healing, Transwell and tube formation assay were performed to identify the invasion, migration and angiogenesis of glioma cells, respectively. TargetScan database predicted the targeted binding between miR-484 and CDKN2A, which was verified by dual luciferase reporter gene assay. Western blot and qRT-PCR were performed to detect the expression of VEGF, E-cadherin, N-cadherin and Vimentin in glioma cells. CDKN2A was low-expressed in glioma tissue/cells as compared to paracancer tissue/astrocytes, and was strongly associated to the poor prognosis of glioma. Further studies found that down-regulation of CDKN2A could promote migration, invasion and angiogenesis of glioma cells. Besides, miR-484 was high-expressed in glioma cells compared to astrocytes. Up-regulation of miR-484 could enhance migration, invasion and angiogenesis of glioma cells. In addition, up-regulated miR-484 suppressed the expression of E-cadherin, and promoted the expression of N-cadherin, Vimentin and VEGF. However, there was negative regulation of miR-484 and CDKN2A, and CDKN2A could partially offset the effect of miR-484. MiR-484 promoted cell migration, invasion and angiogenesis by inhibiting CDKN2A expression.

PLK4 initiates crosstalk between cell cycle, cell proliferation and macrophages infiltration in gliomas.

Tumor immune microenvironment plays an important role in tumorigenesis and metastasis. Polo-like kinases 4 (PLK4) is a crucial regulatory factor in the process of cell cycle, and its abnormal regulation often leads to a variety of diseases including tumorigenesis. We have previously explored the function of PLK4 in sensitizing chemotherapy in glioma, but there are few studies on the correlation between PLK4 and tumor immune microenvironment. PLK4 was found to be highly expressed in various types of cancers, including glioma and closely related to histological and genetic features in public databases. Kaplan-Meier survival analysis and Cox regression analysis revealed that higher PLK4 expression is associated with poorer prognosis. GO and KEGG functional enrichment analysis showed that PLK4 expression level was significantly correlated with regulation of immune microenvironment, cell cycle and genomic instability. Immune infiltration analysis showed that high expression of PLK4 resulted in reduced infiltration of macrophages. M1 macrophage infiltration assays showed that PLK4 knockdown GBM cell lines promoted the recruitment of M1-type macrophages via altering expression of chemokines. And in intracranial tumor mouse models, PLK4 inhibition increased tumor-infiltrating M1 macrophages. In summary, our results demonstrated the correlation between high PLK4 expression level and malignant progression of gliomas, and the possible involvement of PLK4 in regulation of cell cycle, cell proliferation and macrophages infiltration in gliomas.

Role of COL6A2 in malignant progression and temozolomide resistance of glioma

BackgroundGliomas are one of the most common primary malignant tumors of the central nervous system, and have an unfavorable prognosis. Even combining precise surgery, chemotherapy and radiotherapy, the survival rate is still unsatisfactory. Chemotherapy resistance is one of main reasons for its adverse prognosis. As shown by several studies, glioma stem cells (GSCs) were correlated with radiotherapy/chemotherapy resistance and high relapse rate. This study aimed to find a new biomarker related to GSCs and chemotherapy resistance. MethodsTCGA, CGGA, GSE16011, GSE23806 and GDSC datasets were used to screen the genes related to GSCs, Temozolomide (TMZ) resistance, and survival. In the TCGA, GTEx, GSE16011 and CGGA datasets, mRNA level, prognostic value, and correlation with immune infiltration in the selected genes were analyzed through methods including Kaplan-Meier analysis, Cox analysis, the ESTIMATE algorithm, and the CIBERSORT algorithm. The expression of COL6A2 mRNA and protein in different groups was detected by RT-qPCR and western blot. A MTT assay and flow cytometry were used to measure the effect of COL6A2 on proliferation and apoptosis of glioma cells. ResultsCOL6A2 was positively correlated with glioma stemness and TMZ resistance. Its expression was up-regulated in GBM, and high expression was correlated with adverse prognosis. As shown by Cox analysis, COL6A2 was an independent prognostic factor for glioma. COL6A2 mRNA was increased with the glioma grade. It was over-expressed in MGMT non-methylation and IDH wild-type specimens. The results of in vitro experiments showed that COL6A2 promots proliferation of glioma cells and inhibits their apoptosis. Meanwhile, the expression of COL6A2 in TMZ-resistant glioma cells was significantly higher than that in ordinary glioma cells. As shown by GO and KEGG pathway analysis, COL6A2 was correlated with glioma proliferation, migration, invasion, and immunity. In particular, it was significantly positively correlated with PD-1, PD-L2, PD-L1, B7-H3, CTLA-4, IDO1 and TIM-3 expression, further verifying that it may play an important role in immune response. In addition, COL6A2 might influence immune cell infiltration in the glioma microenvironment. ConclusionCOL6A2 high-expression is an indicator for adverse glioma prognosis, and is correlated with TMZ-resistant and immune response. Meanwhile, it may be a prospective biomarker for treatment.

Microglia and Brain Macrophages as Drivers of Glioma Progression

Evidence is accumulating that the tumour microenvironment (TME) has a key role in the progression of gliomas. Non-neoplastic cells in addition to the tumour cells are therefore finding increasing attention. Microglia and other glioma-associated macrophages are at the centre of this interest especially in the context of therapeutic considerations. New ideas have emerged regarding the role of microglia and, more recently, blood-derived brain macrophages in glioblastoma (GBM) progression. We are now beginning to understand the mechanisms that allow malignant glioma cells to weaken microglia and brain macrophage defence mechanisms. Surface molecules and cytokines have a prominent role in microglia/macrophage-glioma cell interactions, and we discuss them in detail. The involvement of exosomes and microRNAs forms another focus of this review. In addition, certain microglia and glioma cell pathways deserve special attention. These "synergistic" (we suggest calling them "Janus") pathways are active in both glioma cells and microglia/macrophages where they act in concert supporting malignant glioma progression. Examples include CCN4 (WISP1)/Integrin α6β1/Akt and CHI3L1/PI3K/Akt/mTOR. They represent attractive therapeutic targets.

GAS5 attenuates the malignant progression of glioma stem-like cells by promoting E-cadherin.

It has been widely reported that glioma stem-like cells (GSCs) serve a crucial role in the malignant progression of glioma. In particular, recent studies have reported that long non-coding RNAs (lncRNAs) are closely associated with glioma development. However, the underlying molecular regulatory mechanistic role of GSCs remains poorly understood. The present study established two highly malignant glioma stem-like cell lines from clinical surgical specimens. In these, it was found that the lncRNA growth arrest-specific 5 (GAS5) expression was downregulated in GSCs and high-grade glioma tissues, compared with normal human astrocyte cells (NHAs) and normal brain tissues, respectively, which also showed a positive correlation with patient survival. Functional assays revealed that knocking down GAS5 expression promoted the proliferation, invasion, migration, stemness, and tumorigenicity of GSGs, while suppressing their apoptosis. Mechanistically, GAS5 directly sponged miR-23a, which in turn functioned as an oncogene by inhibiting E-cadherin, through the assays of reverse transcription-quantitative PCR (RT-qPCR) and luciferase reports. In addition, rescue experiments demonstrated that GAS5 could promote the expression and function of E-cadherin in a miR-23a-dependent manner. Collectively, these data suggest that GAS5 functions as a suppressor in GSCs by targeting the miR-23a/E-cadherin axis, which may be a promising therapeutic target against glioma.

Interfering with CALCRL expression inhibits glioma proliferation, promotes apoptosis, and predicts prognosis in low-grade gliomas

CALCRL is involved in a variety of key biological processes, including cell proliferation, apoptosis, angiogenesis, and inflammation. However, the role of CALCRL in glioma remains unknown. The purpose of this study was to investigate the effect of differential CALCRL expression on the malignant progression of glioma and its value in glioma prognosis. Sequencing data from glioma and normal tissues were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, and the downloaded data were statistically analyzed using bioinformatics tools and the corresponding R package. The expression of CALCRL in normal brain tissue and different grades of glioma tissue was detected by pathological and immunohistochemical staining of clinical glioma specimens. The expression of CALCRL in different glioma cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR), and the U87 cell line with high expression was selected to construct the CALCRL knockdown model by transfection with short hairpin (shRNA). The cell proliferation ability was detected by Celigo assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the ability of cell clone formation was detected by clone formation assay, and the level of apoptosis was detected by flow cytometry. The expression of CALCRL in glioma was significantly upregulated compared with that of normal tissue, especially in low-grade glioma (LGG) compared to glioblastoma, and the differential expression of CALCRL correlated significantly with the prognosis of LGG. Clinical pathology and immunohistochemistry showed that the expression of CALCRL was related to the pathological grade of glioma, and the highest expression was found in World Health Organization (WHO) grade Ⅲ glioma. The results of qRT-PCR showed that CALCRL expression was highest in the U87 cell line. After knockdown of CALCRL expression, the proliferation and clonogenic ability of U87 cells were significantly decreased, and the apoptosis rate was significantly increased. CALCRL is highly expressed in LGG. Interfering with CALCRL expression inhibits glioma cell proliferation and promotes apoptosis, and thus has potential as a biomarker and therapeutic target for the prognosis of those with LGGs.

Expression of TIM-1 in patients with glioma and its correlation with clinicopathological features.

The objective of this research was to investigate the expression of TIM-1 in patients with glioma and its correlation with clinicopathological features. The clinical data of 79 patients with gliomas in our hospital from February 2016 to February 2020 were selected as the research objects of this experiment. TIM-1 detection kit, ELISA and eliysion kit were used to detect TIM-1. The expression of TIM-1 was detected by an automatic immunohistochemical analyzer. Results revealed that the expression of TIM-1 in glioma tissue was abnormal, and its level was significantly higher than that in normal tissue adjacent to the tumor. The high level of TIM-1 expression in gliomas was correlated with KPS grade and histological grade., The expression level of TIM-1 in glioma tissue can affect the survival rate of patients and become one of the independent risk factors of glioma. In conclusion, the histological grade and KPS grade of glioma are related to the high-level expression of TIM-1, which not only suggests that TIM-1 is involved in the occurrence and malignant progression of glioma but also suggests that the malignant change of glioma has a high risk.

Activation of embryonic/germ cell-like axis links poor outcomes of gliomas

BackgroundIt is unclear which core events drive the malignant progression of gliomas. Earlier studies have revealed that the embryonic stem (ES) cell/early PGC state is associated with tumourigenicity. This study was designed to investigate the role of ES/PGC state in poor outcomes of gliomas.MethodsCrispr-Cas9 technology, RT–PCR and animal experiments were used to investigate whether PGC-like cell formation play crucial roles in the tumorigenicity of human glioma cells. Bioinformatic analysis was used to address the link between ES/PGC developmental axis and glioma overall outcomes.ResultsHere, our findings showed that germ cell-like cells were present in human gliomas and cultured glioma cells and that the formation of germ cell-like cells was essential for glioma tumours. Bioinformatic analysis showed that the mRNA levels of genes related to embryonic/germ cell development could be detected in most gliomas. Our findings showed that the activation of genes related to reprogramming or the germ cell-like state alone seemed to be insufficient to lead to a malignant prognosis, whereas increased mRNA levels of genes related to the activation of the embryonic/germ cell-like cycle (somatic PGC-EGC-like cycle and somatic parthenogenetic embryo-like cycle) were positively correlated with malignant prognoses and poor clinical outcomes of gliomas. Genes related to the embryonic/germ cell cycle alone or in combination with the WHO grade or 1p19q codeletion status could be used to subdivide gliomas with distinct clinical behaviours.ConclusionTogether, our findings indicated that a crucial role of germ cell-like cell formation in glioma initiation as well as activation of genes related with the parthenogenetic embryo-like cycle and PGC-EGC-like cycle link to the malignant prognosis and poor outcomes of gliomas, which might provide a novel way to better understand the nature of and develop targeted therapies for gliomas as well as important markers for predicting clinical outcomes in gliomas.

MicroRNA-433-3p enhances chemosensitivity of glioma to cisplatin by downregulating NR5A2.

We attempted to investigate influence of microRNA-433-3p on malignant progression of glioma and identify its molecular mechanism, thus laying groundwork for glioma management. Expression data along with clinical data of glioma were accessed from the TCGA database for differential and survival analyses to look for the target differentially expressed genes. Quantitative reverse transcriptase PCR (qRT-PCR) and western blot were utilized to assess NR5A2 mRNA and protein expression in different glioma cell lines, respectively. MTT, Transwell assay, and flow cytometry were carried out to assay the impact of NR5A2 on behaviors of glioma cells in vitro. Bioinformatics analysis was used to identify the upstream microRNA of NR5A2 in glioma, while dual-luciferase and western blot assays were used to detect binding of microRNA and NR5A2. Chemosensitivity of glioma cells was evaluated by cisplatin cytotoxicity test. NR5A2 was upregulated in both glioma tissues and cell lines. Dual-luciferase assay result showed binding site of microRNA-433-3p on NR5A2 mRNA 3'UTR, and microRNA-433-3p reduced NR5A2 expression. Cell assays revealed that silencing NR5A2 could hamper proliferation, invasion, and migration and enhance chemosensitivity to cisplatin while promoting glioma cell apoptosis and blocking glioma cells in G0/G1 phase. Rescue experiments also indicated that microRNA-433-3p suppressed glioma malignant progression via inhibiting NR5A2. MicroRNA-433-3p which is significantly poorly expressed in glioma targets NR5A2 to suppress glioma malignant progression and enhance chemosensitivity to cisplatin.

CUX2 prevents the malignant progression of gliomas by enhancing ADCY1 transcription.

Gliomas are one of the most prevalent brain tumors. This study sought to elucidate the mechanism of CUX2 in glioma development via ADCY1. CUX2 and ADCY1 expression in glioma predicted by bioinformatics analysis. Subsequent to gain- and loss-of-function experiments in glioma cells, cell proliferation was tested by CCK8 and plate clone formation assays, and cell migration and invasion by Transwell assay. The binding between CUX2 and ADCY1 was examined with dual-luciferase gene reporter and ChIP assays. The xenograft mouse model was established to verify the effect of the CUX2/ADCY1 axis on glioma cell growth in vivo. CUX2 and ADCY1 expression was low in glioma. The overexpression of CUX2 repressed the proliferative, migrating, and invasive abilities of glioma cells. Moreover, CUX2 was enriched in the ADCY1 promoter to enhance ADCY1 expression. ADCY1 upregulation diminished glioma cell proliferative, migrating, and invasive properties. Silencing of ADCY1 abrogated and upregulation of ADCY1 promoted the inhibitory influence of CUX2 upregulation on the malignant behaviors of glioma cells in vitro and gliomas cell growth in vivo. Collectively, CUX2 promoted ADCY1 transcription to delay glioma cell migration, proliferation, and invasion.