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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157933-05
Application #
8838732
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Yassin, Rihab R
Project Start
2011-07-05
Project End
2017-04-30
Budget Start
2015-05-01
Budget End
2017-04-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurosurgery
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhou, Aidong; Lin, Kangyu; Zhang, Sicong et al. (2017) Gli1-induced deubiquitinase USP48 aids glioblastoma tumorigenesis by stabilizing Gli1. EMBO Rep 18:1318-1330
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
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
Wang, Zhongyong; Zhang, Sicong; Siu, Timothy L et al. (2015) Glioblastoma multiforme formation and EMT: role of FoxM1 transcription factor. Curr Pharm Des 21:1268-71
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
Xue, Jianfei; Chen, Yaohui; Wu, Yamei et al. (2015) Tumour suppressor TRIM33 targets nuclear ?-catenin degradation. Nat Commun 6:6156

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