Transcriptional regulation of gliomagenesis

描述（申请人提供）：恶性胶质瘤是最常见的原发性脑肿瘤亚型，具有侵袭性和神经破坏性。多形性胶质母细胞瘤（GBM）是最常见的胶质瘤形式，其患者的平均生存时间约为1年，迄今尚无有效的治疗方法。缺乏进展可归因于，至少部分，高度细胞增殖和侵入性。因此，即使在积极的多模式治疗后，入侵的GBM细胞也可能逃脱治疗并导致肿瘤复发。然而，对GBM不受控制的细胞增殖和侵袭的细胞和分子机制知之甚少。基于我们最近的实验结果，我们提出评估FoxM1在人GBM中异常表达的新假设，FoxM1可能通过b-catenin介导的机制引起GBM细胞的增殖和侵袭，从而促进致瘤性。为了验证这一假设，我们建议评估FoxM1与b-catenin合作表达b-catenin靶基因的功能；foxm1 -b-连环蛋白相互作用在胶质瘤细胞增殖和侵袭中的作用；foxm1 -b-连环蛋白相互作用在维持GBM细胞致瘤性中的重要作用。此外，我们建议确定Wnt信号通路在GBM中FoxM1过表达中的作用。如果这项资助申请的具体目标完成，我们不仅将了解一般和胶质瘤中失调的b-catenin激活的新机制，以及通过失调的b-catenin和FoxM1表达/功能发生胶质瘤的新机制，而且还将了解FoxM1是否可以作为潜在的治疗靶点。这些信息将具有潜在的高翻译影响。从长远来看，我们的研究可能会导致分子靶点的验证，这些靶点可用于设计有效的策略，以在临床上控制这种致命疾病。

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.