STAT3 REGULATION OF GLIOBLASTOMA PATHOGENESIS

STAT3 对胶质母细胞瘤发病机制的调节

• 批准号: 8578360
• 负责人: AZAD BONNI
• 金额: $ 32.21万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578360
• 关键词: STAT3; REGULATION; GLIOBLASTOMA; PATHOGENESIS

The long-term objectives of the proposal are to elucidate the molecular mechanisms that drive the pathogenesis of glioblastoma, the most common and aggressive primary brain tumor. We are taking a novel neurodevelopmental perspective to the study of glioblastoma pathogenesis. Glioblastoma tumors are thought to arise from the transformation of astrocytes or their precursor cells, the neural stem cells. During brain development, the transcription factor STAT3 plays a critical role in the regulation of neural stem cell fate specification including their differentiation into astrocytes. The central hypothesis of the project is that deregulation of STAT3 signaling contributes to glioblastoma pathogenesis. Using a rigorous mouse genetics approach, we have discovered that STAT3 plays opposing oncogenic and tumor suppressive roles in astrocytes depending on the mutational profile of the tumor. The major genetic alterations of deficiency of the tumor suppressor PTEN and expression of the oncogenic protein EGFRvIII may mark distinct sets of glioblastoma tumors. Remarkably, we have found that STAT3 suppresses cell transformation downstream of PTEN deficiency, whereas STAT3 behaves in an oncogenic manner downstream of EGFRvIII in astrocytes. We have also found that STAT3 represses IL8 transcription in PTEN-deficient glioblastoma cells and thereby inhibits their proliferation and invasiveness. Our findings raise fundamental questions on STAT3's role and mechanisms in glial malignancy. What is the mechanism by which STAT3 mediates the ability of EGFRvIII to induce astrocyte transformation? How does STAT3 repress IL8 transcription in PTEN-deficient glioblastoma cells? What is the role of STAT3 signaling in the biology of human glioblastoma cancer stem cells? We propose to address these questions by achieving the following three specific aims, (1) determine the mechanism by which STAT3 mediates EGFRvIII-induced astrocyte transformation by identifying the genes that operate downstream of STAT3 in this pathobiological response, (2) identify the transcriptional regulators that couple the STAT3 signal to IL8 repression in glioblastoma cells, and (3) determine the function of STAT3 in the malignant potential of glioblastoma cancer stem cells in vitro and in vivo. The proposed experiments represent an important set of experiments that will significantly improve our understanding of the transcriptional mechanisms that govern glioblastoma pathogenesis. The proposed studies should also lay the foundation for potential identification of novel therapeutic strategies in patient-tailored treatment of glioblastoma.

该提案的长期目标是阐明驱动细胞凋亡的分子机制。 胶质母细胞瘤是最常见和最具侵袭性的原发性脑肿瘤。我们要把一本小说 神经发育的角度来研究胶质母细胞瘤的发病机制。胶质母细胞瘤被认为 由星形胶质细胞或其前体细胞神经干细胞转化而成。在脑 转录因子STAT3在神经干细胞命运的调节中起着关键作用 说明，包括其分化成星形胶质细胞。该项目的核心假设是， STAT3信号转导的失调有助于胶质母细胞瘤的发病。使用严格的小鼠遗传学 通过这种方法，我们发现STAT3在肿瘤发生中起着相反的致癌和肿瘤抑制作用。 星形胶质细胞取决于肿瘤的突变情况。主要的遗传改变是缺乏的， 肿瘤抑制基因PTEN和致癌蛋白EGFRvIII的表达可能标志着不同的肿瘤细胞凋亡。 胶质母细胞瘤值得注意的是，我们已经发现STAT3抑制细胞转化的下游， PTEN缺陷，而STAT3在星形胶质细胞中以EGFRvIII下游的致癌方式表现。 我们还发现，STAT3抑制PTEN缺陷型胶质母细胞瘤细胞中IL 8的转录， 抑制它们的增殖和侵袭性。我们的发现提出了关于STAT3作用的基本问题， 神经胶质恶性肿瘤的机制。STAT3介导EGFRvIII的能力的机制是什么？ 诱导星形胶质细胞转化？STAT3如何抑制PTEN缺陷型胶质母细胞瘤中IL 8的转录 细胞？STAT3信号在人类胶质母细胞瘤干细胞生物学中的作用是什么？我们 建议通过实现以下三个具体目标来解决这些问题：（1）确定 STAT3介导EGFRvIII诱导的星形胶质细胞转化的机制， 在这种病理生物学反应中，STAT3的下游起作用，（2）鉴定转录调节因子， 将STAT3信号与胶质母细胞瘤细胞中的IL 8抑制偶联，以及（3）确定STAT3在胶质母细胞瘤细胞中的功能。 胶质母细胞瘤癌干细胞在体外和体内的恶性潜能。拟议的实验代表了 一组重要的实验，将大大提高我们对转录的理解， 控制胶质母细胞瘤发病的机制。拟议的研究还应奠定基础， 在胶质母细胞瘤的患者定制治疗中识别新的治疗策略的可能性。