A20 Promotes Glioma Stem Cell Mediated Tumorigenesis

项目摘要 胶质母细胞瘤是成人中最常见和最具侵袭性的原发性脑肿瘤， 最佳治疗的中位生存期只有14个月。多 所需的新疗法可能来自对生物学和生物学特性的日益认识， 肿瘤细胞亚群的分子特性，可以自我更新和重演， 亲代肿瘤这些癌症干细胞仍然存在争议，由于不断发展的 然而，一些报告表明， 胶质母细胞瘤含有癌症干细胞，这些胶质瘤干细胞有助于 治疗抗性和肿瘤血管生成。我们现在证明细胞 生存调节因子A20/肿瘤坏死因子a诱导蛋白3是胶质瘤干细胞 有助于胶质瘤生长的靶点。虽然非常有限而且常常是矛盾的 关于A20在脑肿瘤中的表达和功能，我们发现， 与非干细胞胶质瘤相比，GSC始终表达升高水平的A20 细胞靶向GSC中A20的表达降低了它们的生长， 细胞周期停滞增加、凋亡增加和自我更新减少。靶向 GSC中的A20增加了携带人胶质瘤异种移植物的小鼠的存活率， 对神经胶质瘤表达数据库的分析表明，A20 mRNA的增加与神经胶质瘤的发生有关。 神经胶质瘤患者的存活率很低基于这一背景，我们假设A20 促进神经胶质瘤生长和复发，部分原因是维持癌干 细胞表型我们建议阐明A20的分子和生物学作用， 神经胶质瘤干细胞生物学为神经胶质瘤患者确定新靶点 治疗

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.