The Roles of MicroRNAs in Glioblastoma

描述(申请人提供)：胶质母细胞瘤(GBM)是成人中最常见和最具侵袭性的原发脑瘤，目前是无法治愈的，平均生存期略高于最初诊断的一年。虽然在了解与GBM进展相关的基因变化方面已经取得了重大进展，但在基于对患者病理特征和预后后果之间的分子联系的分析所收集的信息之前，需要了解更多的知识，才能开发出更好的治疗这种疾病的方法。在这方面，我们检测了CD133+胶质瘤干细胞/肿瘤启动细胞(GSCs)对低氧条件反应相关的microRNAs表达谱的变化。我们的初步数据表明，CD133+GSCs在低氧培养条件下的一组microRNAs的表达谱显示出显著的变化，这表明它们可能在这些细胞对低氧应激的生物学反应中发挥作用。此外，对该组中的几个miRNAs的表达进行操作后，CD133+GSCs在裸鼠颅内环境中的异种移植生长以及培养中的生长和神经球的形成都发生了显著的变化，表明这些miRNAs调控着这些细胞的特定病理活动。同时，我们已经获得了低氧诱导miRNA加工调节的证据，揭示了低氧引起miRNA表达谱变化的信号通路的分子本质。为了进一步探索这些发现，我们提出了三个具体的目标：1.继续确定选定的一些与GSC中缺氧反应相关的microRNAs的功能作用和作用机制。2.利用已建立的转基因小鼠模型，探讨这些已鉴定的miRNAs在肿瘤形成/进展中的作用。3.研究DROSHA复合体对GSCs缺氧反应的调节机制。我们将使用细胞培养和小鼠模型来实现这些目标。

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults that is currently incurable with an average survival of slightly more than one year past the initial diagnosis. Although significant progress has been made in understanding the genetic changes associated with the progression of GBM, much more needs to be learned before better treatment for this disease can be developed based on information gathered from analysis of molecular links between pathological features and prognostic consequences of patients. In this regard, we have examined changes in the expression profiles of microRNAs associated with responses to hypoxic conditions by CD133+ glioma stem/tumor initiating cells (GSCs). Our preliminary data indicated that a set of microRNAs exhibits significant alterations in their expression profile in response to hypoxic culturing conditions by the CD133+ GSCs, suggesting that they may play roles in the biological responses of these cells to the hypoxic stress. Furthermore, manipulation on the expression of a selected few miRNAs from this group led to significant changes in the xenograft growth of CD133+ GSCs inoculated into the intracranial environment in nude mice, as well as their growth and neurosphere formation in culture, indicating that those miRNAs modulate specific pathological activities of those cells. In the meantime, we have obtained evidence indicative of hypoxia-induced regulation of miRNA processing, uncovering new insights into the molecular nature of the signaling pathway by which hypoxia acts to elicit changes in miRNA expression profile. To further explore these findings, we propose three specific aims: 1. Continue the determination of the functional roles and acting mechanisms of a selected number of microRNAs whose expression is correlated with hypoxic response in GSCs. 2. Explore the roles of those identified miRNAs on tumor formation/progression using an established transgenic mouse model. 3. Examine the regulatory mechanisms that modulate miRNA processing by the Drosha complex in response to hypoxia in GSCs. We will employ both cell culture and mouse models to accomplish these objectives.