lncRNA regulation of glioblastoma progression and therapeutic resistance

项目摘要 胶质母细胞瘤（GBM）是一种无法治愈的原发性脑肿瘤，其特征在于 缺氧和明显的抗辐射能力。胶质瘤干细胞样细胞（GSC）是一种高度恶性的胶质瘤。 细胞亚群对标准细胞毒性治疗具有高度抗性。GSC有一个 高自我更新能力，经常位于缺氧地区，使他们更 甚至很难被辐射杀死因此，GSC在疾病复发中发挥重要作用。 最近发现长链非编码RNA（lncRNA）在癌症中失调。 lncRNA具有多种功能，包括调节基因表达。我们发现 lncRNALucat1是GSC对缺氧反应重要调节因子。Lucat1经常 在GBM中过表达，并且与侵袭性IDH wt亚型的不良预后相关。 我们的数据支持Lucat 1是由缺氧诱导的，并形成一个正调控环， 促进HIF1a信号传导。在功能上，我们的数据支持Lucat 1有助于维持GSC， 促进肿瘤生长。在这项研究中，我们建议确定一种机制， Lucat 1调节HIF 1信号传导（Aim 1）并评估Lucat 1在GSC维持中的功能 和肿瘤进展（Aim 2）。这些研究将揭示一种新的重要机制， 其中Lucat 1的低氧诱导驱动GSC介导的肿瘤发生。如果成功，我们的发现 将提供一种新的治疗方法，靶向GSC在缺氧，以改善GBM控制。 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。 表达高水平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.