Malignant glioma, the most common primary brain tumor subtype, is aggressive and neurologically destructive. The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. The lack of progress can be attributed, at least in part, to the highly cellular proliferation and invasive. Thus, even after aggressive multimodal therapy, the invading GBM cells can escape the therapy and cause a tumor relapse. However, little is known about the cellular and molecular mechanisms underlying uncontrolled cellular proliferation and invasion of GBM. Based on our recent experimental results, we propose to evaluate the novel hypothesis that FoxM1, which is abnormally expressed in human GBM, causes the cellular proliferation and invasion of GBM cells, possibly through a b-catenin-mediated mechanism, and, thus contribute to tumorigenicity. To test this hypothesis, we propose to evaluate the function of FoxM1 in the cooperation with b-catenin in the expression of b-catenin target genes;the function of FoxM1-b-catenin interaction in cell proliferation and invasion of glioma cells;and the essential role of FoxM1-b-catenin interaction in maintaining the tumorigenicity of GBM cells. Moreover, we propose to determine the role of Wnt signaling pathway in the FoxM1 overexpression in GBM. If the Specific Aims of this grant application are completed, not only will we understand new mechanisms for the dysregulated b-catenin activation in general and in glioma, and for gliomagenesis through dysregulated b-catenin and FoxM1 expression/function, but also will we learn whether FoxM1 can serve as a potential therapeutic target. This information will have potentially high translational impact. In the long term, our study may lead to the validation of molecular targets that can be used in designing effective strategies to control this deadly disease in clinics.
The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. If the Specific Aims of this grant application are completed, not only will we understand a new mechanism of GBM tumorigenesis through abnormal cell growth and invasion of GBM cells controlled by the interaction of FoxM1 and b-catenin, but we will also learn whether FoxM1 or its target b-catenin can function as potential therapeutic targets. This information will have potential translational impact. In the long term, our study may lead to the identification of molecular targets that can be used in designing effective strategies to control this deadly disease.
|Zhang, Sicong; Zhao, Boxuan Simen; Zhou, Aidong et al. (2017) m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. Cancer Cell 31:591-606.e6|
|Zhou, Aidong; Lin, Kangyu; Zhang, Sicong et al. (2016) Nuclear GSK3? promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. Nat Cell Biol 18:954-966|
|Xue, Jianfei; Zhou, Aidong; Wu, Yamei et al. (2016) miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis. Cancer Res 76:4293-304|
|Chen, Yaohui; Li, Yu; Xue, Jianfei et al. (2016) Wnt-induced deubiquitination FoxM1 ensures nucleus ?-catenin transactivation. EMBO J 35:668-84|
|Morris, Saint-Aaron L; Huang, Suyun (2016) Crosstalk of the Wnt/?-catenin pathway with other pathways in cancer cells. Genes Dis 3:41-47|
|Xue, Jianfei; Chen, Yaohui; Wu, Yamei et al. (2015) Tumour suppressor TRIM33 targets nuclear ?-catenin degradation. Nat Commun 6:6156|
|Li, Zhiwei; Jia, Zhiliang; Gao, Yong et al. (2015) Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness. Clin Cancer Res 21:844-53|
|Xue, Jianfei; Zhou, Aidong; Tan, Christina et al. (2015) Forkhead Box M1 Is Essential for Nuclear Localization of Glioma-associated Oncogene Homolog 1 in Glioblastoma Multiforme Cells by Promoting Importin-7 Expression. J Biol Chem 290:18662-70|
|Yu, Guanzhen; Zhou, Aidong; Xue, Jianfei et al. (2015) FoxM1 promotes breast tumorigenesis by activating PDGF-A and forming a positive feedback loop with the PDGF/AKT signaling pathway. Oncotarget 6:11281-94|
|Gong, Ai-Hua; Wei, Ping; Zhang, Sicong et al. (2015) FoxM1 Drives a Feed-Forward STAT3-Activation Signaling Loop That Promotes the Self-Renewal and Tumorigenicity of Glioblastoma Stem-like Cells. Cancer Res 75:2337-48|
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