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学科主题: 基础医学
题名:
Molecular Targeting of TRF2 Suppresses the Growth and Tumorigenesis of Glioblastoma Stem Cells
作者: Bai, Yun1,2; Lathia, Justin D.3; Zhang, Peisu2; Flavahan, William3; Rich, Jeremy N.4; Mattson, Mark P.2
关键词: cancer stem cells ; glioblastoma ; telomeres ; transcriptional repression
刊名: GLIA
发表日期: 2014-10-01
DOI: 10.1002/glia.22708
卷: 62, 期:10, 页:1687-1698
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Neurosciences
研究领域[WOS]: Neurosciences & Neurology
关键词[WOS]: ADHESION MOLECULE ; GENE-EXPRESSION ; ADJUVANT TEMOZOLOMIDE ; GLIOMA-CELLS ; HUMAN BRAIN ; REST ; CANCER ; TUMOR ; P53 ; DNA
英文摘要:

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 beta 3-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.

语种: 英语
所属项目编号: 81272432 ; 31070948
项目资助者: National Natural Sciences Foundation of China ; Intramural Research Program of the National Institute on Aging (NIH)
WOS记录号: WOS:000340846600009
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/54577
Appears in Collections:基础医学院_细胞生物学系_期刊论文

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作者单位: 1.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Cell Biol, Beijing 100191, Peoples R China
2.Natl Inst Aging Intramural Res Program, Neurosci Lab, Baltimore, MD USA
3.Cleveland Clin Fdn, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44195 USA
4.Cleveland Clin Fdn, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44195 USA

Recommended Citation:
Bai, Yun,Lathia, Justin D.,Zhang, Peisu,et al. Molecular Targeting of TRF2 Suppresses the Growth and Tumorigenesis of Glioblastoma Stem Cells[J]. GLIA,2014,62(10):1687-1698.
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