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Cheng W.,China Medical University at Heping | Cheng W.,Chinese Glioma Cooperative Group | Li M.,Beijing Neurosurgical Institute | Li M.,Capital Medical University | And 11 more authors.
Journal of Neurosurgery

Objective This study investigated the role and prognostic value of heat shock proteins (HSPs) in glioma. Methods Data from 3 large databases of glioma samples (Chinese Glioma Genome Atlas, Repository for Molecular Brain Neoplasia Data, and GSE16011), which contained whole-genome messenger RNA microarray expression data and patients' clinical data, were analyzed. Immunohistochemical analysis was performed to validate protein expression in another set of 50 glioma specimens. Results Of 28 HSPs, 11 were overexpressed in high-grade glioma (HGG) compared with low-grade glioma. A univariate Cox analysis revealed that HSPB11 has significant prognostic value for each glioma grade, which was validated by a Kaplan-Meier survival analysis. HSPB11 expression was associated with poor prognosis and was independently correlated with overall survival (OS) in HGG. This study further explored the combined role of HSPB11 and other molecular markers in HGG, such as isocitrate dehydrogenase 1 (IDH1) mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. HSPB11 expression was able to refine the prognostic value of IDH1 mutation in patients with HGG. However, when combined with MGMT promoter methylation status, among patients with a methylated MGMT promoter, those with lower levels of HSPB11 expression had longer OS and progression-free survival than patients with higher levels of HSPB11 expression or with an unmethylated MGMT promoter. Moreover, within the MGMT promoter methylation group, patients with low levels of HSPB11 expression were more sensitive to combined radiochemotherapy than those with high levels of HSPB11 expression, which may explain why some patients with HGG with a methylated MGMT promoter show tolerance to radiochemotherapy. Conclusions HSPB11 was identified as a novel prognostic marker in patients with HGG. Together with MGMT promoter methylation status, HSPB11 expression can predict outcome for patients with HGG and identify those who would most benefit from combined radiochemotherapy. © AANS, 2016. Source

Wang X.,Capital Medical University | Wang K.,Zhejiang University | Han L.,Tianjin Medical University | Han L.,Chinese Glioma Cooperative Group | And 14 more authors.
Cancer Letters

The transcriptional regulator PRDM1 controls cell-fate decisions and has been implicated in human tumorigenesis as a tumor suppressor. However, its pathological role in glioma remains elusive. In this study, we showed that PRDM1 protein levels were inversely correlated with the pathological grade of gliomas and were predictive of patient survival in a retrospective analysis. Restored expression of PRDM1 inhibited proliferation and suppressed invasion by glioma cells. Mechanistic investigation revealed that PRDM1 attenuated glioma malignancy by negatively modulating Wnt/β-catenin signaling and this modulation was dependent on the Wnt inhibitor Dkk1. Using bioinformatics and biological approaches, we found that PRDM1 was a direct target of miR-30a-5p, and PRDM1 dysfunction was attributable to miR-30a-5p-mediated repression. Our results provide evidence that PRDM1 deficiency contributes to the phenotype maintenance and pathogenesis of gliomas. © 2013 Elsevier Ireland Ltd. Source

Qian X.,Tianjin University | Ren Y.,Tianjin Medical University | Shi Z.,Tianjin Medical University | Shi Z.,Chinese Glioma Cooperative Group | And 7 more authors.
Molecular Pharmaceutics

Down-regulation of microRNA-21 (miR-21) can induce cell apoptosis and reverse drug resistance in cancer treatments. In this study, we explored the most effective schedule of the miR-21 inhibitor (miR-21i) and Temozolomide (TMZ) combined treatment in human glioma cells. Three tumor cell lines, U251 phosphatase and tensin homologue (PTEN) mutant, LN229 (PTEN wild-type), and U87 (PTEN loss of function), were subjected to evaluate the antitumor effects of deigned treatments (a predose of miR-21i for 4/8 h and then a subsequent TMZ treatment, a predose of TMZ for 4/8 h and then a subsequent miR-21i treatment, or a concomitant treatment) in vitro. A synergistic antiproliferative and proapoptotic activity was only obtained in U251 and U87 cells when a predose was administered for 4 h before the treatment of the other therapeutic agent, while the best antitumor effect in LN229 cells was achieved by using the concomitant treatment. Our data indicate that the effect of sequence and timing of administration is dependent on the PTEN status of cell lines. The best suppression effect was achieved by a maximal inhibition of STAT3 and phosphorylated STAT3, in PTEN loss of function cells. Our results reveal that both the sequence and the timing of administration are crucial in glioma combination therapy. © 2012 American Chemical Society. Source

Zhang R.,Nanjing Medical University | Luo H.,Nanjing Medical University | Wang S.,Nanjing Medical University | Chen W.,Nanjing Medical University | And 20 more authors.

Background: Increasing evidence has indicated that microRNAs (miRNAs) are strongly implicated in the initiation and progression of glioblastoma multiforme (GBM). Here, we identified a novel tumor suppressive miRNA, miR-377, and investigated its role and therapeutic effect for GBM. Methods: MiRNA global screening was performed on GBM patient samples and adjacent nontumor brain tissues. The expression of miR-377 was detected by real-time reverse-transcription PCR. The effects of miR-377 on GBM cell proliferation, cell cycle progression, invasion, and orthotopic tumorigenicity were investigated The therapeutic effect of miR-377 mimic was explored in a subcutaneous GBM model. Western blot and luciferase reporter assay were used to identify the direct and functional target of miR-377. Results: MiR-377 was markedly downregulated in human GBM tissues and cell lines. Overexpression of miR-377 dramatically inhibited cell growth both in culture and in orthotopic xenograft tumor models, blocked G1/S transition, and suppressed cell invasion in GBM cells. Importantly, introduction of miR-377 could strongly inhibit tumor growth in a subcutaneous GBM model. Subsequent investigation revealed that specificity protein 1 (Sp1) was a direct and functional target of miR-377 in GBM cells. Silencing of Sp1 recapitulated the antiproliferative and anti-invasive effects of miR-377, whereas restoring the Sp1 expression antagonized the tumor-suppressive function of miR-377. Finally, analysis of miR-377 and Sp1 levels in human GBM tissues revealed that miR-377 is inversely correlated with Sp1 expression. Conclusion: These findings reveal that miR-377/Sp1 signaling that may be required for GBM development and may consequently serve as a therapeutic target for the treatment of GBM. © The Author(s) 2014. Source

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