Signal Integration of Transcriptional Pathways in Gliomagenesis

描述（申请人提供）：胶质瘤侵袭性强，侵袭性强，易对化疗和放疗产生耐药性。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。正是由于GB的侵袭性和增生性，使得肿瘤复发且无法治愈。导致这种恶性行为的分子变化尚不清楚。本研究的目标是获得关于GBM生长和侵袭的致病途径及其机制整合的明确知识，这对于开发GBM患者的有效治疗方法至关重要。先前的研究表明FoxM1表达增加是GBM中最常见的改变之一。我们最近的研究表明，人胶质母细胞瘤组织中FoxM1蛋白的表达水平与患者的生存率呈负相关。此外，FoxM1似乎对胶质瘤的生长至关重要。然而，FoxM1过表达的潜在机制尚不清楚。因此，我们建议研究FoxM1在GBM中表达失调的分子机制（目的1）。我们将确定Wnt/b-catenin通路异常激活是否导致GBM细胞中FoxM1过表达。先前的研究表明，b-catenin的组成性激活不是由于肿瘤抑制因子APC的失活或b-catenin的突变。为了研究b-catenin/ tcf介导的转录在GBM中激活的原因，我们将确定核FoxM1在增强b-catenin/TCF4/LEF-1转录活性中的作用和机制（目的2）。此外，Stat3通路是胶质瘤发生的一个节点枢纽，但其表达和激活升高的机制尚不清楚。我们的初步数据表明，FoxM1过表达可能通过b-catenin介导的机制导致GBM细胞中Stat3的表达和激活失调。因此，我们提出确定细胞核FoxM1对Stat3的调控及其在FoxM1促进肿瘤发展中的作用（Aim 3）。如果这项资助申请的具体目标完成，我们不仅将了解这些主要途径的信号整合的新机制，而且我们将了解信号整合对胶质瘤发展和进展的生物学和临床影响。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。因此,

DESCRIPTION (provided by applicant): Gliomas are aggressive, highly invasive, and easily become resistant to chemotherapy and radiotherapy. 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. It is the highly invasive and proliferative nature of GB rendering the tumor relapse and incurable. The molecular changes leading to this malignant behavior are poorly understood. The goal of this proposal is to gain definitive knowledge on the causative pathways and their mechanistic integration underlying GBM growth and invasion, which is critical for developing effective therapeutic modalities for GBM patients. Previous studies have shown that increased expression of FoxM1 is one of the most frequent alterations in GBM. Our recent study has shown that the level of FoxM1 protein expression in human glioblastoma tissues is inversely correlated with patient survival. Moreover, FoxM1 appears to be essential to glioma growth. However, the underlying mechanisms for FoxM1 overexpression are unknown. Therefore, we propose to investigate the molecular mechanisms underlying the dysregulated FoxM1 expression in GBM (Aim 1). We will determine whether the aberrant Wnt/b-catenin pathway activation causes FoxM1 overexpression in GBM cells. Previous studies have indicated that constitutive activation of b-catenin is not due to inactivation of the tumor suppressor APC or mutations in b-catenin. To investigate the causes for the activation of b-catenin/TCF-mediated transcription in GBM, we will determine the role and mechanisms of nuclear FoxM1 in enhancing b-catenin/TCF4/LEF-1 transcriptional activity (Aim 2). Furthermore, Stat3 pathway is a nodal hub of gliomagenesis, while the mechanisms underlying its elevated expression and activation are unknown. Our preliminary data indicated that FoxM1 overexpression causes the dysregulated Stat3 expression and activation in GBM cells, possibly through a b-catenin-mediated mechanism. Therefore, we propose to determine the regulation of Stat3 by nuclear FoxM1 and its function in FoxM1-promoted tumor development (Aim 3). If the specific aims of this grant application are completed, not only we will understand new mechanisms for the signaling integration of those major pathways, but also we will learn the biological and clinical impacts of the signaling integration on glioma development and progression. 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. Therefore, the findings from our proposed studies will contribute to a better understanding of the molecular mechanisms of glioma development and progression and help identify potential targets for novel therapeutic strategies against malignant glioma.