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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 (IP 3 R)-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., (Copyright © 2021. Published by Elsevier Inc.)

BACKGROUND Circular RNAs (circRNAs) are widely expressed in mammals and can regulate the development and progression of human tumors. has_circ_0015758 (circ-CFH) is an exon circRNA transcript from the GRCh37/hg19 fragment of chromosome 1 and is homologous to the protein-coding gene complement factor H (CFH). Currently, the function of circ-CFH in glioma remains unclear. MATERIAL AND METHODS In our study, circ-CFH, miR-149, and Akt1 mRNA expression levels were analyzed by qRT-PCR assays. To investigate the function of circ-CFH in cell proliferation, circ-CFH knockdown models were established by using circ-CFH siRNAs. Cell proliferation abilities were measured by CCK-8 and colony formation assays and in vivo experiments. In addition, the interaction between circ-CFH and miR-149 was assessed by luciferase reporter assays. RESULTS Circ-CFH expression was significantly upregulated in glioma tissue and was correlated with tumor grade. Circ-CFH expression levels were also markedly higher in U251 and U373 glioma cell lines. Circ-CFH knockdown inhibited cell proliferation and colony formation abilities. Luciferase assays indicated that circ-CFH functions as a miR-149 sponge and inhibits its function in U251 and U373 cells. Subsequently, AKT1 was identified as a direct target of the circ-CFH/miR-149 axis. CONCLUSIONS Circ-CFH promotes glioma progression by sponging miR-149 and regulating the AKT1 signaling pathway. The circ-CFH/miR-149/AKT1 regulation axis may be a potential target for glioma therapy.

Glioma is the most common malignant brain tumor in adults and represents one of the most aggressive and life‑threatening types of cancer in humans. Increasing studies have revealed that microRNAs are abnormally expressed in various types of human cancer, and have oncogenic or tumor suppressive roles, which depend primarily on the type of cancer. The present study aimed to investigate the expression level and effects of microRNA‑186 (miR‑186) on glioma, and its underlying molecular mechanism. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis was performed to detect the expression of miR‑186 in glioma tissues and cell lines. Cell proliferation and invasion were assessed using MTT and cell invasion assays, respectively. Bioinformatics analysis and a luciferase reporter assay were performed to identify insulin‑like growth factor 1 receptor (IGF‑1R) as a novel target gene of miR‑186. The mRNA expression level of IGF‑1R was also measured using RT‑qPCR analysis. The association between miR‑186 and the expression of IGF‑1R was evaluated using Spearman's correlation anal-ysis. Furthermore, the regulatory effects of miR‑186 on the mRNA and protein expression of IGF‑1R were determined using RT‑qPCR and western blot analyses. Finally, the biological effects of the underexpression IGF‑1R on glioma cells were investigated. The results showed that miR‑186 was significantly downregulated in glioma tissues and cell lines. Inducing the expression of miR‑186 suppressed glioma cell proliferation and invasion. IGF‑1R was confirmed as a direct target gene of miR‑186. In addition, the mRNA expression of IGF‑1R was upregulated and inversely correlated with that of miR‑186 in glioma tissues. The effects of IGF‑1R‑knockdown on glioma cell proliferation and invasion were similar to the effects induced by the overexpression of miR‑186. These findings demonstrated that miR‑186 acted as a tumor suppressor by targeting IGF‑1R in glioma, suggesting miR‑186 may be a potential therapeutic target for the treatment of this disease.

Background: Glioma accounts for the majority of primary malignant brain tumors in adults., Methods: Glioma specimens and normal brain tissues were analyzed for the expression levels of GSK-3β and p-GSK-3β (Ser9) by tissue microarray analysis (TMA) and Western blotting. Glioma cells over-expressing GSK-3β were used to analyze biological functions both in vitro and in vivo., Results: The levels of p-GSK-3β (Ser9), but not total GSK-3β, are significantly up-regulated in glioma tissues compared to normal tissues, and are significantly correlated with the glioma grades. Ectopic expression of GSK-3β decreased the phosphorylation levels of mTOR and p70S6K1; and inhibited β-catenin, HIF-1α and VEGF expression. Forced expression of GSK-3β in glioma cells significantly inhibited both tumor growth and angiogenesis in vivo., Conclusions: These results reveal that GSK-3β regulates mTOR/p70S6K1 signaling pathway and inhibits glioma progression in vivo; its inactivation via p-GSK-3β (Ser9) is associated with glioma development, which is new mechanism that may be helpful in developing GSK-3β-based treatment of glioma in the future.

Background: Attention dysfunction has been observed among many kinds of nervous system diseases, including glioma. This study aimed to investigate the correlation between glioma localization, malignancy, postoperative recovery time and attention deficit., Methods: A total of 45 patients with glioma who underwent surgical resection and 18 healthy volunteers were enrolled. The attention network test, digital span test, color trail test II and Stroop test were used to detect the characteristics of attention deficit., Results: Orientation network dysfunction was detected in the parietal lobe tumor group, and execution network deficit was detected in both the frontal and parietal lobe groups, while no significant difference was detected in the temporal lobe group compared to healthy controls. The high-grade glioma group (grade III-IV) exhibited more serious functional impairment than the low-grade group (grade I-II). No significant correlation was observed between postoperative recovery time and attention impairment., Conclusions: High-grade glioma patients suffer more severe attention impairment. In addition, the frontal and parietal lobe glioma patients suffer attention dysfunction in dissimilar manner. These findings will provide important guidance on the care of glioma patients after therapy.

MicroRNA-335 (miR-335), as a transcript of genomic region chromosome 7q32.2, acts as a tumor suppressor or tumor promoter in various human malignancies. Especially, it has been reportedly shown to be an oncogene in human glioma cell line in vitro, but its expression in human glioma tissues is not yet determined. The aim of this study was to investigate the clinical significance of miR-335 expression in glioma. MiR-335 expression in human gliomas and nonneoplastic brain tissues was measured by real-time quantitative RT-PCR assay. The association of miR-335 expression with clinicopathological factors and prognosis of glioma patients was statistically analyzed. The expression level of miR-335 in glioma tissues was significantly higher than that in corresponding nonneoplastic brain tissues (P < 0.001). In addition, high miR-335 expression was significantly associated with a higher WHO grade (P = 0.001). Survival analysis demonstrated that patients with high miR-335 expression tumors had significantly shorter survival times than those with low miR-335 expression tumors (P = 0.01) and that miR-335 was an independent prognostic factor (P = 0.02). Especially, subgroup analyses according to tumor histologic grade revealed that the mean survival time of patients with high grade (III-IV) was significantly worse for high miR-335 expression group than for low miR-335 expression group (P = 0.002), but no significant difference was found for patients with WHO grade I-II (P = 0.16). These results indicated that miR-335 expression was increased in human gliomas and was associated with advanced tumor progression. Furthermore, miR-335 expression was demonstrated for the first time to be an independent marker for predicting the clinical outcome of patients with gliomas.

A disintegrin and metalloprotease 8 (ADAM8) has been shown to be expressed in various cancer types, and its expression was associated with advanced progression of several tumors. However, little is known about ADAM8 in human gliomas. Therefore, we here evaluated the correlation of ADAM8 expression with the clinicopathological features and prognosis in the patients with gliomas. Immunohistochemistry and western blot were used to investigate the expression of ADAM8 protein, respectively, in 128 patients with gliomas. The expression levels of ADAM8 in glioma tissues were significantly higher (P = 0.002) than those in non-neoplastic brain tissues according to the immunohistochemistry analysis. In addition, a high level of ADAM8 expression was significantly more common in glioma tissues with advanced grade than those with low grade (P = 0.01), which were in line with the results of western blot analysis (P = 0.01). Moreover, the increased expression of ADAM8 was significantly correlated with low Karnofsky performance score (KPS) (P = 0.008), frequent intra-tumor necrosis (P = 0.01), and poor overall survival (P = 0.008). Furthermore, multivariate analysis identified the expression levels of ADAM8 (P = 0.01) and intra-tumor necrosis (P = 0.03) to be independent prognostic factors. These findings suggest for the first time that ADAM8 is frequently overexpressed in human gliomas and is closely associated with poor clinical outcome.

Gliomas are the most common primary intracranial tumors. Understanding the molecular basis of gliomas' progression is required to develop more effective therapies. The Wnt/β-catenin signaling cascade is an important signal transduction pathway in human cancers. Although, overactivation of this pathway is a hallmark of several forms of cancer, little is known about its role in human gliomas. Here, we aimed to determine the clinical significance of Wnt/β-catenin pathway components in gliomas. Immunohistochemical staining was performed to detect the expression patterns of Wnt1, β-catenin and Cyclin D1 in the biopsies from 96 patients with primary gliomas. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of patients. Cytoplasmic staining pattern of Wnt1, membranous, cytoplasmic and nuclear accumulation of β-catenin, and nuclear localization of Cyclin D1 were demonstrated by immunohistochemical staining. The Wnt1 expression significantly correlated with the expression of Cyclin D1 (P < 0.0001). The ratio of tumors with a cytoplasmic-nuclear pattern or a cytoplasmic pattern of β-catenin was significantly higher in Wnt1-positive (P < 0.01) and Cyclin D1-positive (P < 0.01) tumors than in Wnt1-negative and Cyclin D1-negative tumors, respectively. The protein expression levels of Wnt1, β-catenin and Cyclin D1 were all positively correlated with the Karnofsky performance scale (KPS) score and World Health Organization (WHO) grades of patients with gliomas. Furthermore, Wnt1, cytoplasmic-nuclear β-catenin and Cyclin D1 status were all the independent prognostic factors for glioma patients (P = 0.01, 0.007 and 0.005, respectively). These results provide convincing evidence that the Wnt/β-catenin pathway correlated closely with the progression of gliomas and might be a novel prognostic marker for this neoplasm.

Human glioma is a malignancy that has no effective systemic therapy. Focal adhesion kinase (FAK) is overexpressed in various invasive and metastatic tumor cells. To investigate its prognostic value in human gliomas, which currently is unknown, we examined the expression patterns of FAK and its activated form, phospho-FAK (FAK pY397), and analyzed the correlation between their expression and prognosis in patients with gliomas. Immunohistochemical staining was performed to detect FAK and phospho-FAK expression patterns in the biopsies from 96 patients with primary gliomas. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of patients. As a result, the immunohistochemical analysis revealed that FAK and phospho-FAK both were associated significantly with the Karnofsky performance scale (KPS) score and World Health Organization (WHO) grades of patients with gliomas. Especially, the positive expression rates of FAK and phospho-FAK were significantly higher in patients with a higher grade (P = 0.01 and 0.02, respectively) and a lower KPS score (P = 0.006 and 0.008, respectively). The patients with FAK positive expression correlated with a poor prognosis of human gliomas (P = 0.006) as well as phospho-FAK (P = 0.01). The survival rate of the patients with FAK+/phospho-FAK+ expression was the lowest (P < 0.05), and conjoined expressions of FAK/phospho-FAK were an independent prognostic indicator of human gliomas (P < 0.05). In conclusion, the results suggest that the elevated expression of FAK and phospho-FAK is an important feature of human glioma. A combined detection of FAK/phospho-FAK coexpression may benefit us in the prediction of the prognosis of human glioma., (Copyright 2010 Mosby, Inc. All rights reserved.)

Glioma is the most common and malignant tumor of the central nervous system. Glioblastoma (GBM) is the most aggressive glioma, with a poor prognosis and no effective treatment because of its high invasiveness, metabolic rate, and heterogeneity. The tumor microenvironment (TME) contains many tumor-associated macrophages (TAMs), which play a critical role in tumor proliferation, invasion, metastasis, and angiogenesis and indirectly promote an immunosuppressive microenvironment. TAM is divided into tumor-suppressive M1-like (classic activation of macrophages) and tumor-supportive M2-like (alternatively activated macrophages) polarized cells. TAMs exhibit an M1-like phenotype in the initial stages of tumor progression, and along with the promotion of lysing tumors and the functions of T cells and NK cells, tumor growth is suppressed, and they rapidly transform into M2-like polarized macrophages, which promote tumor progression. In this review, we discuss the mechanism by which M1- and M2-polarized macrophages promote or inhibit the growth of glioblastoma and indicate the future directions for treatment. [ABSTRACT FROM AUTHOR]

AIMS: To evaluate the prognostic and clinicopathological features of glioma with BRMS1L expression. METHODS: Total 120 glioma samples were obtained as discovery cohort. CGGA, GSE and TCGA datasets were obtained as validation sets. Furthermore, Kaplan-Meier survival and multivariate Cox analysis were used to evaluate the survival distributions. Moreover, the functional role of BRMS1L was also analyzed by transwell assay. RESULTS: In the discovery cohort, decreased BRMS1L expression was significantly associated with high-grade glioma as well as the higher mortality in survival analysis (log-rank test, p < 0.01). And the three validation cohorts showed the similar results. Furthermore, BRMS1L act as an independent prognostic factor in glioblastoma patients. Additionally, functional assay showed that ectopic of BRMS1L suppressed glioma cells’ invasion. CONCLUSION: BRMS1L plays as an anti-oncogene in GBM and indicates a new potential therapeutic target. [ABSTRACT FROM AUTHOR]