Transcriptional regulation of gliomagenesis

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DESCRIPTION (provided by applicant): 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.