The Fox M1 in Human Glioma Development and Progression

描述（由申请人提供）：恶性胶质瘤是最常见的脑肿瘤，具有极高的发病率和死亡率。我们研究的长期目标是揭示神经胶质瘤发生和发展的分子机制，目前对此知之甚少。最近使用寡核苷酸微阵列分析的研究表明，叉头盒M1 （FoxM1）转录因子的改变是恶性胶质瘤中最常见的分子改变之一。我们的初步结果表明FoxM1的表达水平与胶质瘤的分级直接相关。FoxM1在永生化正常人类星形胶质细胞（NHAs）中的强制表达足以将细胞转化为胶质瘤细胞。在裸鼠模型中，间变性星形细胞瘤细胞中FoxM1的表达增强促进了其向胶质母细胞瘤的进展，而FoxM1的表达抑制了胶质母细胞瘤细胞的非锚定生长。此外，由转染foxm1的细胞产生的胶质瘤具有高度增殖、侵袭性和血管生成性。转染foxm1的胶质瘤细胞活化Akt、VEGF和MMP-2的表达增加，而转染foxm1 - sirna的胶质瘤细胞活化Akt的表达降低。在这里，我们建议确定FoxM1异常表达在胶质瘤发生和进展中的因果关系和机制。我们假设FoxM1的异常表达通过促进不受控制的细胞增殖、侵袭和血管生成来促进胶质瘤的发展和进展。我们的具体目的是：1)确定FoxM1表达改变对胶质瘤生物学的影响。我们将通过FoxM1- sirna抑制系统、FoxM1过表达细胞系和体内小鼠模型来确定FoxM1对胶质瘤细胞增殖、侵袭和血管生成的重要贡献。2)确定FoxM1过表达与Rb缺失在胶质瘤发生发展中的合作关系。我们将在pRb通路失活的遗传小鼠胶质瘤模型中研究FoxM1转基因表达是否加速胶质瘤的形成并促进胶质瘤的进展。3) FoxM1过表达是否通过激活Akt通路参与胶质瘤的发生和进展。4)明确FoxM1调控胶质瘤侵袭和血管生成的分子机制。FoxM1调节侵袭和血管生成的机制将被研究，特别关注它如何调节MMP-2和VEGF基因的表达。我们提出的研究结果将有助于更好地理解胶质瘤发生和进展的分子机制，并将确定针对恶性胶质瘤的新治疗策略的潜在靶点。

DESCRIPTION (provided by applicant): Malignant gliomas are the most common brain tumors and are associated with extremely high rates of morbidity and mortality. The long-term goal of our research is to reveal the molecular mechanisms underlying glioma development and progression, of which very little is currently known. Recent studies using oligonucleotide microarray analysis have shown that alteration to the Forkhead box M1 (FoxM1) transcription factor is one of the most frequent molecular alterations in malignant gliomas. Our preliminary results indicate a direct correlation between FoxM1 expression level and the grade of gliomas. Enforced FoxM1 expression in immortalized normal human astrocytes (NHAs) was sufficient to transform the cells into glioma cells. Enforced FoxM1 expression in anaplastic astrocytoma cells promoted their progression into glioblastomas in nude mouse models, and suppressed FoxM1 expression inhibited the anchorage-independent growth of glioblastoma cells. Moreover, gliomas arisen from FoxM1-transfected cells were highly proliferative, invasive, and angiogenic. FoxM1-transfected glioma cells had increased expression of activated Akt, VEGF and MMP-2, whereas FoxM1-siRNA-transfected glioma cells had decreased expression of activated Akt. Here, we propose to determine the causal effects and mechanisms of aberrant FoxM1 expression on glioma development and progression. We hypothesize that aberrant expression of FoxM1 contributes to glioma development and progression by promoting uncontrolled cell proliferation, invasion, and angiogenesis. Our Specific Aims are 1) To determine the effect of altered FoxM1 expression on glioma biology. We will determine the critical contribution of FoxM1 to glioma cell proliferation, invasion, and angiogenesis in vitro and in vivo by using the FoxM1-siRNA inhibition system, FoxM1-overexpressing cell lines, and in vivo mouse models. 2) To determine the cooperation between FoxM1 overexpression and Rb loss in glioma development and progression. We will investigate whether FoxM1 transgene expression accelerates glioma formation and promotes glioma progression in a genetic mouse glioma model with an inactivated pRb pathway. 3) To determine whether FoxM1 overexpression contributes to glioma development and progression via activation of Akt pathway. 4) To identify the molecular mechanisms by which FoxM1 regulates glioma invasion and angiogenesis. The mechanisms of FoxM1 regulating invasion and angiogenesis will be investigated with a particular focusing on how it regulates the expression of the MMP-2, and VEGF genes. The findings from our proposed studies will contribute to a better understanding of the molecular mechanisms of glioma development and progression and will identify potential targets for novel therapeutic strategies against malignant glioma.