lncRNA regulation of glioblastoma progression and therapeutic resistance

lncRNA对胶质母细胞瘤进展和治疗耐药的调节

基本信息

批准号：
10391009
负责人：
Jennifer S Yu
金额：
$ 54.32万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10391009
关键词：
Animals Area Binding Biological Assay Brain Neoplasms CRISPR interference Cell Maintenance Cell Nucleus Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Disease Epigenetic Process Gene Expression Regulation Genes Genetic Transcription Glioblastoma Glioma Goals Growth Human Hypoxia Individual Knowledge Left Lung diseases Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Nuclear Organoids Pathway interactions Patients Penetration Play Primary Brain Neoplasms Prognosis Proteins Pulmonary Emphysema RNA purification Radiation Radiation Oncologist Recurrence Refractory Regulation Renal Cell Carcinoma Resistance Response Elements Ribonucleoproteins Role Signal Transduction Smoking Transactivation Untranslated RNA Work Xenograft procedure chemotherapeutic agent cytotoxic design digital epigenetic regulation genetic manipulation genomic locus hypoxia inducible factor 1 improved in vivo knock-down leukemia lung cancer cell mouse model nano-string normoxia novel novel therapeutic intervention overexpression patient response promoter radiation response radioresistant recruit response self-renewal stem cells stem-like cell stemness therapeutic target therapy resistant transcriptome transcriptome sequencing treatment strategy tumor tumor growth tumor progression tumorigenesis

项目摘要

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.

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，其特征是缺氧和对辐射的明显抗性。神经胶质瘤干细胞（GSC）是高度恶性肿瘤对标准细胞毒性处理高度抗性的细胞亚群。 GSC有一个自我更新的高容量，经常位于低氧区域，使它们更多甚至很难用辐射杀死。因此，GSC在疾病复发中起着重要作用。最近发现长期非编码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 LNCRNA Lucat1是GSC对缺氧反应的重要调节剂。 Lucat1经常在GBM中过表达，与侵略性IDH WT亚型的预后不良有关。我们的数据支持Lucat1是由缺氧诱导的，并形成了积极的调节循环促进HIF1A信号传导。从功能上，我们的数据支持Lucat1有助于维护GSC 缺氧并促进肿瘤生长。在这项研究中，我们建议确定一种机制 LUCAT1调节HIF1信号传导（AIM 1）并评估Lucat1在GSC维护中的功能和肿瘤进展（AIM 2）。这些研究将通过 Lucat1的低氧诱导驱动GSC介导的肿瘤发生。如果成功，我们的发现将为靶向缺氧的GSC提供一种新的治疗方法，以改善GBM控制。这种治疗策略可能会扩展到其他癌症，包括吸烟相关的肺表达高水平Lucat1的癌症和肾细胞癌。