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，很容易对化疗和放射治疗产生抗药性。多形性胶质母细胞瘤(GBM)是最常见的胶质瘤，其患者的平均生存期约为1年，目前尚无有效的治疗方法。它是高侵袭性和增殖性的GB，导致肿瘤复发和无法治愈。导致这种恶性行为的分子变化还知之甚少。这项建议的目的是获得关于GBM生长和侵袭的致病途径及其机制整合的明确知识，这对于开发有效的GBM患者的治疗方式至关重要。以往的研究表明，FOXM1的高表达是GBM中最常见的改变之一。我们最近的研究表明，FOXM1蛋白在人脑胶质母细胞瘤组织中的表达水平与患者的生存期呈负相关。此外，FOXM1似乎对胶质瘤的生长是必不可少的。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(目标1)。我们将确定Wnt/b-catenin途径的异常激活是否导致GBM细胞中FOXM1的过度表达。先前的研究表明，b-catenin的结构性激活不是由于肿瘤抑制基因APC的失活或b-catenin的突变。为了探讨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(目标2)。此外，STAT3通路是胶质瘤发生的节点枢纽，但其表达和激活上调的机制尚不清楚。我们的初步数据表明，FOXM1的过度表达导致了GBM细胞中STAT3表达和激活的失调，可能是通过b-连环蛋白介导的机制。因此，我们建议确定核FOXM1对STAT3的调节及其在FOXM1促进肿瘤发展中的作用(目标3)。如果完成此次拨款申请的具体目标，我们不仅将了解这些主要途径的信号整合的新机制，而且还将了解信号整合在胶质瘤发生发展中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标的验证，这些靶标可以用于设计有效的策略，在临床上控制这种致命的疾病。因此， 我们提出的研究结果将有助于更好地理解胶质瘤发生发展的分子机制，并有助于确定针对恶性胶质瘤的新治疗策略的潜在靶点。

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.