A20 Promotes Glioma Stem Cell Mediated Tumorigenesis

A20 促进神经胶质瘤干细胞介导的肿瘤发生

• 批准号: 8288833
• 负责人: Anita Borton Hjelmeland
• 金额: $ 25.28万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288833
• 关键词: Adjuvant; Adult; Animal Model; Apoptosis; Apoptosis Inhibitor; Apoptotic; BIRC5 gene; Binding; Biological; Brain Neoplasms; Cell Cycle Arrest; Cell Death; Cell Survival; Cells; DNA Damage; DNA damage checkpoint; Data; Databases; Endothelial Cells; Excision; Gene Cluster; Gene Targeting; Glioblastoma; Glioma; Growth; Human; Hypoxia; Link; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; Microarray Analysis; Modeling; Molecular; Mus; Nature; Operative Surgical Procedures; Patients; Pattern; Phenotype; Phosphorylation; Primary Brain Neoplasms; Property; Proteins; Radiation; Radiation Induced DNA Damage; Recurrence; Reporting; Resistance; Response Elements; Role; Signal Pathway; Signal Transduction; Stem cells; TNF gene; Therapeutic; Therapeutic Studies; Transcriptional Activation; Tumor Angiogenesis; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factors; Xenograft procedure; angiogenesis; bHLH-PAS factor HLF; base; cancer stem cell; cell growth regulation; chemotherapy; genetic manipulation; inhibitor/antagonist; neoplastic cell; novel; promoter; response; self-renewal; small hairpin RNA; stem cell biology; temozolomide; transcription factor; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY Glioblastomas are the most common and aggressive primary brain tumor in adults, with a median survival of only fourteen months with the best available treatments. Much needed novel therapies may arise from increased appreciation of the biological and molecular properties of subset of tumor cells which can self-renew and recapitulate the parental tumor. These cancer stem cells remain controversial due to the evolving understanding of their nature: however, a number of reports have demonstrated that glioblastomas contain cancer stem cells and that these glioma stem cells contribute to therapeutic resistance and tumor angiogenesis. We now demonstrate that the cell survival regulator A20/Tumor Necrosis Factor a Inducible Protein 3 is a glioma stem cell target which contributes to glioma growth. Although very limited and often contradictory data exists regarding the expression and function of A20 in brain tumors, we find that GSCs consistently express elevated levels of A20 in comparison to non-stem glioma cells. Targeting the expression of A20 in GSCs reduces their growth in association with increased cell cycle arrest, elevated apoptosis, and decreased self-renewal. Targeting A20 in GSCs increased the survival of mice bearing human glioma xenografts, and analysis of a glioma expression database indicates that increased A20 mRNA correlates with poor glioma patient survival. Based on this background, we hypothesize that A20 promotes glioma growth and recurrence due, in part, to maintenance of a cancer stem cell phenotype. We propose to elucidate the molecular and biological role of A20 in glioma stem cell biology in an effort to determine novel targets for glioma patient therapies.

项目总结 胶质母细胞瘤是成人中最常见和最具侵袭性的原发脑瘤， 使用最好的治疗方法，中位生存期只有14个月。大有可为 所需的新疗法可能产生于对生物和 具有自我更新和重现功能的肿瘤细胞亚群的分子特性 亲代肿瘤。这些癌症干细胞由于进化而仍然存在争议 对其性质的理解：然而，一些报告表明 胶质母细胞瘤含有肿瘤干细胞，这些胶质瘤干细胞有助于 治疗耐药与肿瘤血管生成。我们现在证明了细胞 生存调节因子A20/肿瘤坏死因子诱导蛋白3是一种胶质瘤干细胞 促进胶质瘤生长的靶点。虽然非常有限，而且经常自相矛盾 关于A20在脑肿瘤中的表达和功能的数据，我们发现 与非干胶质瘤相比，胶质干细胞持续表达高水平的A20 细胞。靶向A20在GSCs中的表达与其生长抑制相关 细胞周期停滞增加，细胞凋亡率增加，自我更新减少。瞄准 GSCs中的A20可提高荷人胶质瘤异种移植瘤小鼠的存活率 对一个神经胶质瘤表达数据库的分析表明，A20mRNA的增加与 脑胶质瘤患者存活率较低。基于这一背景，我们假设A20 促进神经胶质瘤的生长和复发，部分原因是癌症干细胞的维持 细胞表型。我们建议阐明A20在细胞周期中的分子和生物学作用。 胶质瘤干细胞生物学为胶质瘤患者确定新靶点的努力 治疗。