The Roles of MicroRNAs in Glioblastoma

描述（由申请人提供）：胶质母细胞瘤（GBM）是成人中最常见和最具侵袭性的原发性脑肿瘤，目前无法治愈，初次诊断后平均生存期略超过一年。虽然在理解与GBM进展相关的遗传变化方面取得了重大进展，但在根据从分析患者病理特征和预后后果之间的分子联系中收集的信息开发更好的治疗这种疾病之前，还需要了解更多。在这方面，我们研究了与CD 133+胶质瘤干细胞/肿瘤起始细胞（GSC）对缺氧条件的反应相关的microRNA表达谱的变化。我们的初步数据表明，一组microRNA的表达谱显着改变，以响应缺氧培养条件下的CD 133 + GSCs，这表明他们可能在这些细胞的生物反应，以缺氧应激中发挥作用。此外，对该组中选定的几种miRNA表达的操作导致接种到裸鼠颅内环境中的CD 133 + GSC的异种移植物生长以及它们在培养物中的生长和神经球形成的显著变化，表明这些miRNA调节这些细胞的特定病理活性。与此同时，我们已经获得了缺氧诱导的miRNA加工调节的证据，揭示了缺氧引起miRNA表达谱变化的信号通路的分子本质的新见解。为了进一步探索这些发现，我们提出了三个具体目标：1。继续确定选定数量的microRNA的功能作用和作用机制，其表达与GSC中的缺氧反应相关。2.使用已建立的转基因小鼠模型探索这些鉴定的miRNA在肿瘤形成/进展中的作用。3.检查调节Drosha复合物对GSC中缺氧反应的miRNA加工的调节机制。我们将采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.