The Skaggs Institute of Chemical Biology and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell Stem Cell. 2010 Jan 8;6(1):37-47. doi: 10.1016/j.stem.2009.11.002.
Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer associated with a very poor prognosis. Recently, the initiation and growth of GBM has been linked to brain tumor-initiating cells (BTICs), which are poorly differentiated and share features with neural stem cells (NSCs). Here we describe a kinome-wide RNA interference screen to identify factors that control the tumorigenicity of BTICs. We identified several genes whose silencing induces differentiation of BTICs derived from multiple GBM patients. In particular, knockdown of the adaptor protein TRRAP significantly increased differentiation of cultured BTICs, sensitized the cells to apoptotic stimuli, and negatively affected cell cycle progression. TRRAP knockdown also significantly suppressed tumor formation upon intracranial BTIC implantation into mice. Together, these findings support a critical role for TRRAP in maintaining a tumorigenic, stem cell-like state.
多形性胶质母细胞瘤（GBM）是一种高度侵袭性的脑癌，预后非常差。最近，GBM 的发生和生长与脑肿瘤起始细胞（BTICs）有关，BTICs 分化不良，与神经干细胞（NSCs）具有共同特征。在这里，我们描述了一个激酶组 RNA 干扰筛选，以确定控制 BTIC 致瘤性的因素。我们鉴定了几个基因，其沉默诱导源自多个 GBM 患者的 BTIC 分化。特别是，衔接蛋白 TRRAP 的敲低显著增加了培养的 BTIC 的分化，使细胞对凋亡刺激敏感，并对细胞周期进程产生负面影响。TRRAP 敲低也显著抑制了颅内 BTIC 植入小鼠后的肿瘤形成。总之，这些发现支持了 TRRAP 在维持致瘤性、干细胞样状态中的关键作用。
