Signal Integration of Transcriptional Pathways in Gliomagenesis

描述（由申请人提供）：胶质瘤具有侵袭性，高度侵袭性，容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的性质，使肿瘤复发和不可治愈。导致这种恶性行为的分子变化知之甚少。 该提案的目标是获得有关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患者的有效治疗方式至关重要。以前的研究表明，FoxM 1表达增加是GBM中最常见的改变之一。我们最近的研究表明，FoxM 1蛋白在人胶质母细胞瘤组织中的表达水平与患者的生存率呈负相关。此外，FoxM 1似乎对胶质瘤生长至关重要。然而，FoxM 1过表达的潜在机制尚不清楚。因此，我们建议研究GBM（Aim 1）中FoxM 1表达失调的分子机制。我们将确定异常的Wnt/β-连环蛋白通路激活是否导致GBM细胞中FoxM 1过表达。以前的研究表明，组成性激活的b-连环蛋白是不是由于失活的肿瘤抑制APC或突变的b-连环蛋白。为了研究B-catenin/TCF介导的GBM转录激活的原因，我们将确定核FoxM 1在增强B-catenin/TCF 4/LEF-1转录活性中的作用和机制（目的2）。此外，Stat 3通路是胶质瘤发生的节点枢纽，而其表达和激活的机制尚不清楚。我们的初步数据表明，FoxM 1过表达导致GBM细胞中Stat 3表达和激活失调，可能是通过β-连环蛋白介导的机制。因此，我们建议确定核FoxM 1对Stat 3的调节及其在FoxM 1促进肿瘤发展中的功能（目的3）。 如果这项资助申请的具体目标得以实现，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来控制这种致命的疾病。因此 本研究的发现将有助于更好地理解胶质瘤发生和发展的分子机制，并有助于确定恶性胶质瘤治疗新策略的潜在靶点。

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.