An RNAi Screen Identifies TRRAP as a Regulator of Brain Tumor-Initiating Cell Differentiation
An RNAi Screen Identifies TRRAP as a Regulator of Brain Tumor-Initiating Cell Differentiation
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DOI：
10.1016/j.stem.2009.11.002
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发表时间：
2010-01-08
期刊：
影响因子：
23.9
通讯作者：
Schultz, Peter G.
中科院分区：
文献类型：
--
作者：
Wurdak, Heiko;Zhu, Shoutian;Schultz, Peter G.
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。近年来，基底膜的发生和生长与脑肿瘤起始细胞(BTICs)有关，BTICs分化较差，与神经干细胞(NSCs)具有相同的特征。在这里，我们描述了一种全基因组的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，它们的沉默诱导来自多个GBM患者的BTICs分化。特别是，接头蛋白TRRAP的敲除显著增加了培养的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基因敲除也显著抑制了小鼠脑内BTIC植入后的肿瘤形成。总而言之，这些发现支持TRRAP在维持肿瘤形成的干细胞样状态方面的关键作用。
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.