Signal Integration of Transcriptional Pathways in Gliomagenesis

项目摘要 神经胶质瘤具有侵袭性、高度侵袭性，并且容易对化疗产生耐药性， 放疗多形性胶质母细胞瘤（GBM）患者的平均生存期， 神经胶质瘤的形式，是大约1年，迄今没有有效的治疗。它是一种高度侵入性的， GBM的增殖性质使得肿瘤复发和不可治愈。导致这种情况的分子变化 对恶性行为知之甚少。 该提案的目标是获得有关致病途径及其机制的明确知识， 整合潜在的GBM生长和侵袭，这对于开发有效的治疗药物至关重要。 GBM患者的治疗方法。以前的研究表明，FoxM 1表达增加是导致癌症的原因之一。 GBM最常见的变化。我们最近的研究表明，FoxM 1蛋白的表达水平， 人胶质母细胞瘤组织与患者存活率呈负相关。此外，FoxM 1似乎是 神经胶质瘤生长所必需的然而，FoxM 1过表达的潜在机制尚不清楚。 因此，我们建议研究FoxM 1表达失调的分子机制。 GBM中的表达（Aim 1）。我们将确定异常的Wnt/β-连环蛋白通路激活是否会导致 GBM细胞中的FoxM 1过表达。以前的研究表明，连环蛋白的组成性激活 不是由于肿瘤抑制因子APC的失活或β-连环蛋白的突变。调查的原因 通过研究GBM中<$-catenin/TCF介导的转录的激活，我们将确定 核FoxM 1增强<$-catenin/TCF 4/LEF-1转录活性（Aim 2）。此外，Stat 3 信号通路是胶质瘤发生的节点枢纽，而其表达升高和 激活未知。我们的初步数据表明，FoxM 1过表达导致了细胞凋亡的失调。 Stat 3在GBM细胞中的表达和激活，可能通过连环蛋白介导的机制。因此，我们认为， 我们建议确定Stat 3受核FoxM 1的调节及其在FoxM 1促进的肿瘤中的功能 发展（目标3）。 如果这项拨款申请的具体目标得以完成，我们不仅将了解新的机制 这些主要通路的信号整合，但我们也将学习生物学和临床影响， 信号整合在胶质瘤发生发展中的作用。从长远来看，我们的研究可能会导致 分子靶点的验证，可用于设计有效的策略，以控制这种致命的 疾病在诊所因此，我们建议的研究结果将有助于更好地了解 胶质瘤发展和进展的分子机制，并帮助确定潜在的目标， 针对恶性胶质瘤的新治疗策略。

Project Summary 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 GBM 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/¿-catenin pathway activation causes FoxM1 overexpression in GBM cells. Previous studies have indicated that constitutive activation of ¿-catenin is not due to inactivation of the tumor suppressor APC or mutations in ¿-catenin. To investigate the causes for the activation of ¿-catenin/TCF-mediated transcription in GBM, we will determine the role and mechanisms of nuclear FoxM1 in enhancing ¿-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 ¿-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.