Shi Z.-D.,Tianjin Medical University |
Shi Z.-D.,Key Laboratory of Post Trauma Neuro Repair and Regeneration in the Central Nervous System |
Qian X.-M.,Tianjin University |
Zhang J.-X.,Nanjing Medical University |
And 12 more authors.
CNS Neuroscience and Therapeutics | Year: 2014
Background and Aims: The nuclear localization of β-catenin, a mediator of canonical Wnt signaling, has been indicated in a variety of cancers and is frequently related to tumor progression and metastasis. Therefore, targeting β-catenin is an attractive therapeutic strategy for cancers. Methods: Herein, we identified a natural, small molecule inhibitor of β-catenin signaling, BASI, and evaluated its therapeutic efficacy both in vitro and in orthotopic mouse models of glioma. Results: BASI significantly suppressed proliferation and invasion and induced apoptosis in glioblastoma cells and resulted in the remarkable attenuation of orthotopic tumor growth in vivo. Furthermore, we found that BASI altered the expression of several microRNAs, which mediated the posttranscriptional silencing of β-catenin expression either directly or indirectly through a von Hippel-Lindau (VHL)-mediated β-catenin degradation pattern. Conclusions: Taken together, our findings offer preclinical validation of BASI as a promising new type of β-catenin inhibitor with a mechanism of inhibition that has broad potential for the improved treatment of glioblastoma. © 2014 John Wiley & Sons Ltd.
Liu X.,Tianjin Binhai Neurological Institute |
Chen L.,Tianjin Binhai Neurological Institute |
Jiang Z.,The Fifth Central Hospital of Tianjin |
Wang J.,Tianjin Binhai Neurological Institute |
And 6 more authors.
Experimental and Therapeutic Medicine | Year: 2013
Following emergence of the tumor stem cell theory, the increasing number of related studies demonstrates the theory's growing importance in cancer research and its potential for clinical applications. Few studies have addressed the in vitro or in vivo properties of glioma stem cells from a Han Chinese population. In the present study, surgically obtained glioblastoma tissue was classifed into two subtypes, CD133+ and CD133-. The hierarchy, invasiveness, growth tolerance under low nutrient conditions and colony forming abilities of the tissue samples were analyzed. Additionally, the characteristics of tumor cells transplanted subcutaneously or re-transplanted into nude mice were observed. The results demonstrated that CD133+ glioblastoma cells derived from Han Chinese glioma specimens were more prone to primitive cell differentiation and more invasive than CD133- glioblas-toma cells, leading to increased tumor malignancy compared with CD133- cells. The tumor formation rates of CD133+ and CD133- cells in mice were 26/30 and 2/30, respectively. A comparison of tumor subtypes demonstrated that CD133+ glioblastoma cells had a lower incidence of cell apoptosis in the tumor tissue and higher protein expression levels of Oct4, Sox2, PCNA, EGFR, Ang2, MMP2 and MMP9 compared wit h C D133 - cells. Flow cytometry revealed that in the CD133+ and CD133- glioblastoma cell-induced tumors, the percentage of CD133+ cells was 2.47±0.67 and 0.44±0.14%, respectively. The tumor formation rates following the re-transplantation o f C D13 3 + o r C D133 - tumors into nude mice were 10/10 a nd 4/10, respectively. These findings suggest that the CD133+glioblastoma cell subpopulation has a stronger malignant cell phenotype than the CD133- subpopulation and that its recurrence rate is increased compared with the primitive tumorigenic rate following in vivo transplantation.
Wang Y.,Capital Medical University |
Chen L.,Harbin Medical University |
Bao Z.,Capital Medical University |
Li S.,Capital Medical University |
And 11 more authors.
Oncology Reports | Year: 2011
Activation of signal transducer and activator of trans- cription 3 (STAT3) is associated with poor clinical outcome of glioblastoma (GBM). However, the role of STAT3 in resistance to alkylator-based chemotherapy remains unknown. Here, we retrospectively analyzed the phosphorylated STAT3 (p-STAT3) profile of 68 GBM patients receiving alkylator therapy, identifying p-STAT3 as an independent unfavorable prognostic factor for progression-free and overall survival. Additionally, elevated p-STAT3 expression correlated with resistance to alkylator therapy. In vitro analysis revealed that U251 and U87 human glioma cells were refractory to treatment with the common alkylating agent temozolomide (TMZ), with only a modest impact on AKT and β-catenin activation in the context of high p-STAT3. Inhibition of STAT3 in these cells significantly enhanced the effect of TMZ. Inhibition of STAT3 dramatically decreased the IC50 of TMZ, increasing TMZ-induced apoptosis while up-regulating expression of Bcl-2 and down-regulating expression of Bax. Furthermore, inhibition of STAT3 increased TMZ-induced G0-G1 arrest and decreased Cyclin D1 expression compared to TMZ alone. Together, these results indicate that inhibition of STAT3 sensitizes glioma cells to TMZ, at least in part, by blocking the p-AKT and β-catenin pathways. These findings strongly support the hypothesis that STAT3 inhibition significantly improves the clinical efficacy of alkylating agents.
Sun C.,Tianjin Medical University |
Sun C.,Key Laboratory of Post trauma Neuro repair and Regeneration in the Central Nervous System |
Sun C.,Tianjin Key Laboratory of Injuries |
Wang Q.,Tianjin Medical University |
And 26 more authors.
Neuroscience Bulletin | Year: 2013
The matrix-degrading metalloproteinases (MMPs), particularly MMP-9, play important roles in the pathogenesis and development of malignant gliomas. In the present study, the oncogenic role of MMP-9 in malignant glioma cells was investigated via antisense RNA blockade in vitro and in vivo. TJ905 malignant glioma cells were transfected with pcDNA3.0 vector expressing antisense MMP-9 RNA (pcDNA-ASMMP9), which significantly decreased MMP-9 expression, and cell proliferation was assessed. For in vivo studies, U251 cells, a human malignant glioma cell line, were implanted subcutaneously into 4- to 6-week-old BALB/c nude mice. The mice bearing well-established U251 gliomas were treated with intratumoral pcDNA-AS-MMP9-Lipofectamine complex (AS-MMP-9-treated group), subcutaneous injection of endostatin (endostatin-treated group), or both (combined therapy group). Mice treated with pcDNA (empty vector)-Lipofectamine served as the control group. Four or eight weeks later, the volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity were assayed. We demonstrate that pcDNA-AS-MMP9 significantly decreased MMP-9 expression and inhibited glioma cell proliferation. Volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity in the antisense-MMP-9-treated and therapeutic alliance groups were significantly lower than those in the control group. The results suggest that MMP-9 not only promotes malignant glioma cell invasiveness, but also affects tumor cell proliferation. Blocking the expression of MMP-9 with antisense RNA substantially suppresses the malignant phenotype of glioma cells, and thus can be used as an effective therapeutic strategy for malignant gliomas. © 2013 Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg.