lncRNA regulation of glioblastoma progression and therapeutic resistance

项目总结 胶质母细胞瘤(GBM)是一种无法治愈的原发脑肿瘤，其特点是 低氧和明显的抗辐射能力。胶质瘤干细胞是一种高度恶性的细胞。 对标准细胞毒治疗高度耐药的细胞亚群。GSC有一个 自我更新能力强，经常位于缺氧区，使它们更 即使是用辐射也很难杀死。因此，GSC在疾病复发中起着重要作用。 最近发现，长非编码RNA(LncRNAs)在癌症中存在调控失调。 LncRNAs具有多种功能，包括调节基因表达。我们发现， LncRNA Lucat1是GSC对低氧反应的重要调节因子。卢卡特1号经常 在GBM中高表达，与侵袭性IDH wt亚型预后不良有关。 我们的数据支持Lucat1是由缺氧诱导的，并形成了一个正向调节环路 推广HIF1a信号。从功能上讲，我们的数据支持Lucat1帮助维护GSC 低氧和促进肿瘤生长。在这项研究中，我们建议确定一种机制，通过 Lucat1调节HIF1信号转导(目标1)并评估Lucat1在GSC维持中的作用 和肿瘤进展(目标2)。这些研究将揭示一种新的重要机制，通过 低氧诱导的Lucat1驱动GSC介导的肿瘤发生。如果成功，我们的发现 这将为在缺氧状态下靶向GSCs改善GBM控制提供一种新的治疗途径。 这种治疗策略可能会扩展到其他癌症，包括吸烟相关的肺癌。 高水平表达Lucat1的癌症和肾细胞癌。

PROJECT SUMMARY Glioblastoma (GBM) is an incurable primary brain tumor that is characterized by regions of hypoxia and marked resistance to radiation. Glioma stem-like cells (GSCs) are a highly malignant subpopulation of cells that are highly resistant to standard cytotoxic treatments. GSCs have a high capacity for self-renewal and are frequently located in hypoxic areas, making them more even difficult to kill with radiation. GSCs therefore play an important role in disease recurrence. Long non-coding RNAs (lncRNAs) have recently been found to be dysregulated in cancer. LncRNAs have multiple functions including regulation of gene expression. We have found that the lncRNA Lucat1 is an important regulator of GSC response to hypoxia. Lucat1 is frequently overexpressed in GBM and is associated with poor prognosis in the aggressive IDH wt subtype. Our data support that Lucat1 is induced by hypoxia and forms a positive regulatory loop to promote HIF1a signaling. Functionally, our data support that Lucat1 helps to maintain GSCs in hypoxia and promote tumor growth. In this study, we propose to determine a mechanism by which Lucat1 regulates HIF1 signaling (Aim 1) and assess the function of Lucat1 in GSC maintenance and tumor progression (Aim 2). These studies will reveal a new and important mechanism by which hypoxic induction of Lucat1 drives GSC-mediated tumorigenesis. If successful, our findings will provide a new therapeutic approach for targeting GSCs in hypoxia to improve GBM control. This treatment strategy may be extended to other cancers including smoking-associated lung cancer and renal cell cancer that express high levels of Lucat1.