Bai Yun, Lathia Justin D, Zhang Peisu, Flavahan William, Rich Jeremy N, Mattson Mark P
Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China; Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland.
Glia. 2014 Oct;62(10):1687-98. doi: 10.1002/glia.22708. Epub 2014 Jun 7.
Glioblastoma is the most prevalent primary brain tumor and is essentially universally fatal within 2 years of diagnosis. Glioblastomas contain cellular hierarchies with self-renewing glioblastoma stem cells (GSCs) that are often resistant to chemotherapy and radiation therapy. GSCs express high amounts of repressor element 1 silencing transcription factor (REST), which may contribute to their resistance to standard therapies. Telomere repeat-binding factor 2 (TRF2) stablizes telomeres and REST to maintain self-renewal of neural stem cells and tumor cells. Here we show viral vector-mediated delivery of shRNAs targeting TRF2 mRNA depletes TRF2 and REST from GSCs isolated from patient specimens. As a result, GSC proliferation is reduced and the level of proteins normally expressed by postmitotic neurons (L1CAM and β3-tubulin) is increased, suggesting that loss of TRF2 engages a cell differentiation program in the GSCs. Depletion of TRF2 also sensitizes GSCs to temozolomide, a DNA-alkylating agent currently used to treat glioblastoma. Targeting TRF2 significantly increased the survival of mice bearing GSC xenografts. These findings reveal a role for TRF2 in the maintenance of REST-associated proliferation and chemotherapy resistance of GSCs, suggesting that TRF2 is a potential therapeutic target for glioblastoma.
胶质母细胞瘤是最常见的原发性脑肿瘤，在确诊后2年内基本上普遍致命。胶质母细胞瘤包含具有自我更新能力的胶质母细胞瘤干细胞（GSCs）的细胞层级结构，这些干细胞通常对化疗和放疗具有抗性。GSCs表达大量的阻遏元件1沉默转录因子（REST），这可能导致它们对标准疗法产生抗性。端粒重复结合因子2（TRF2）稳定端粒和REST，以维持神经干细胞和肿瘤细胞的自我更新。在这里，我们展示了病毒载体介导的靶向TRF2 mRNA的短发夹RNA（shRNAs）递送可从患者标本中分离出的GSCs中耗尽TRF2和REST。结果，GSC增殖减少，有丝分裂后神经元正常表达的蛋白质（L1细胞粘附分子和β3微管蛋白）水平增加，这表明TRF2的缺失在GSCs中启动了细胞分化程序。TRF2的耗尽还使GSCs对替莫唑胺敏感，替莫唑胺是一种目前用于治疗胶质母细胞瘤的DNA烷化剂。靶向TRF2显著提高了携带GSC异种移植瘤小鼠的存活率。这些发现揭示了TRF2在维持GSCs与REST相关的增殖和化疗抗性中的作用，表明TRF2是胶质母细胞瘤的一个潜在治疗靶点。
