骨形态发生蛋白通路的表观遗传介导功能障碍抑制胶质母细胞瘤起始细胞的分化。
Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells.
作者信息
Lee Jeongwu, Son Myung Jin, Woolard Kevin, Donin Nicholas M, Li Aiguo, Cheng Chui H, Kotliarova Svetlana, Kotliarov Yuri, Walling Jennifer, Ahn Susie, Kim Misuk, Totonchy Mariam, Cusack Thomas, Ene Chibawanye, Ma Hilary, Su Qin, Zenklusen Jean Claude, Zhang Wei, Maric Dragan, Fine Howard A
机构信息
Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
Cancer Cell. 2008 Jan;13(1):69-80. doi: 10.1016/j.ccr.2007.12.005.
Despite similarities between tumor-initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues and by converting otherwise cytostatic signals to proproliferative signals.
尽管具有干细胞样特性的肿瘤起始细胞（TICs）与正常神经干细胞之间存在相似性，但我们推测它们的分化潜能可能存在差异。我们现在证明，在一部分胶质母细胞瘤TICs中，由于EZH2依赖的BMP受体1B（BMPR1B）表观遗传沉默，骨形态发生蛋白（BMP）介导的和睫状神经营养因子（CNTF）介导的Jak/STAT依赖的星形胶质细胞分化均受损。通过转基因表达或启动子去甲基化强制表达BMPR1B可恢复其分化能力并诱导其致瘤性丧失。我们提出，一部分胶质母细胞瘤TICs中BMP发育途径的失调通过使TICs对正常分化信号不敏感以及将原本的细胞生长抑制信号转化为促增殖信号，从而导致其致瘤性。
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