Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells.
Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells.
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DOI：
10.1002/glia.22708
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发表时间：
2014-10
期刊：
影响因子：
6.2
通讯作者：
Mattson, Mark P.
中科院分区：
文献类型：
--
作者：
Bai, Yun;Lathia, Justin D.;Zhang, Peisu;Flavahan, William;Rich, Jeremy N.;Mattson, Mark P.
胶质母细胞瘤是最常见的原发性脑肿瘤，通常在诊断后两年内死亡。胶质母细胞瘤含有自我更新的胶质母细胞瘤干细胞（GSCs），这些干细胞通常对化疗和放疗具有抗性。GSCs表达大量的抑制因子1沉默转录因子（REST），这可能有助于它们对标准治疗的抗性。端粒重复结合因子2 （TRF2）稳定端粒和REST，维持神经干细胞和肿瘤细胞的自我更新。在这里，我们发现病毒载体介导的靶向TRF2 mRNA的shrna递送会耗尽从患者标本中分离的GSCs中的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（L1CAM和β3-微管蛋白）水平升高，表明TRF2的缺失参与了GSC的细胞分化程序。TRF2的缺失也使GSCs对替莫唑胺敏感，替莫唑胺是一种dna烷化剂，目前用于治疗胶质母细胞瘤。靶向TRF2可显著提高移植GSC小鼠的存活率。这些发现揭示了TRF2在维持GSCs的rest相关增殖和化疗耐药中的作用，表明TRF2是胶质母细胞瘤的潜在治疗靶点。
Glioblastoma is the most prevalent primary brain tumor and is essentially universally fatal within two 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.
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影响因子：
3.7
作者：
Dasari VR;Kaur K;Velpula KK;Gujrati M;Fassett D;Klopfenstein JD;Dinh DH;Rao JS
通讯作者：
Rao JS
影响因子：
21.3
作者：
Fujita, Kaori;Horikawa, Izumi;Mondal, Abdul M.;Jenkins, Lisa M. Miller;Appella, Ettore;Vojtesek, Borivoj;Bourdon, Jean-Christophe;Lane, David P.;Harris, Curtis C.
通讯作者：
Harris, Curtis C.
影响因子：
3.7
作者：
Cui YF;Xu JC;Hargus G;Jakovcevski I;Schachner M;Bernreuther C
通讯作者：
Bernreuther C
影响因子：
8.4
作者：
Biroccio, Annamaria;Rizzo, Angela;Gilson, Eric
通讯作者：
Gilson, Eric
影响因子：
4.7
作者：
Hermisson, M;Klumpp, A;Weller, M
通讯作者：
Weller, M