GSK3beta regulates differentiation and growth arrest in glioblastoma.
GSK3beta regulates differentiation and growth arrest in glioblastoma.
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DOI：
10.1371/journal.pone.0007443
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发表时间：
2009-10-13
期刊：
影响因子：
3.7
通讯作者：
Lino MM
中科院分区：
文献类型：
--
作者：
Korur S;Huber RM;Sivasankaran B;Petrich M;Morin P Jr;Hemmings BA;Merlo A;Lino MM
癌症是由一群具有自我更新和无限生长的干细胞特性的细胞驱动的。作为肿瘤内的一个亚群，这些细胞被认为构成了肿瘤细胞库。在癌症中，控制正常干细胞更新的途径被解除了调控。多梳组基因Bmi1是神经干细胞自我更新所必需的，也控制神经元的抗氧化防御，在包括髓母细胞瘤在内的几种癌症中上调。我们发现Bmi1在GBM中持续且高表达。ShRNAs下调Bmi1诱导分化表型，减少干细胞标记物Sox2和Nestin的表达。有趣的是，在原发基底膜中持续表达的糖原合酶激酶3β(GSK3β)的表达也下降。这表明Bmi1和Gsk3β之间存在功能联系。干扰β活性的小干扰RNA、特异性抑制剂SB216763或氯化锂诱导肿瘤细胞分化。此外，肿瘤细胞的凋亡增加，神经球的形成受到损害，克隆形成能力降低，且呈剂量依赖关系。GBM细胞系主要由CD133阴性(CD133-)细胞组成。有趣的是，来自原发肿瘤活检的体外细胞可以鉴定出CD133亚群的细胞，这些细胞表达干细胞标记物，并因GSK3β失活而被耗尽。抑制GSK3的药物，包括精神药物LiCl，可能会耗尽GBM干细胞库，而不受CD133状态的影响。
Cancers are driven by a population of cells with the stem cell properties of self-renewal and unlimited growth. As a subpopulation within the tumor mass, these cells are believed to constitute a tumor cell reservoir. Pathways controlling the renewal of normal stem cells are deregulated in cancer. The polycomb group gene Bmi1, which is required for neural stem cell self-renewal and also controls anti-oxidant defense in neurons, is upregulated in several cancers, including medulloblastoma. We have found that Bmi1 is consistently and highly expressed in GBM. Downregulation of Bmi1 by shRNAs induced a differentiation phenotype and reduced expression of the stem cell markers Sox2 and Nestin. Interestingly, expression of glycogen synthase kinase 3 beta (GSK3β), which was found to be consistently expressed in primary GBM, also declined. This suggests a functional link between Bmi1 and GSK3β. Interference with GSK3β activity by siRNA, the specific inhibitor SB216763, or lithium chloride (LiCl) induced tumor cell differentiation. In addition, tumor cell apoptosis was enhanced, the formation of neurospheres was impaired, and clonogenicity reduced in a dose-dependent manner. GBM cell lines consist mainly of CD133-negative (CD133-) cells. Interestingly, ex vivo cells from primary tumor biopsies allowed the identification of a CD133- subpopulation of cells that express stem cell markers and are depleted by inactivation of GSK3β. Drugs that inhibit GSK3, including the psychiatric drug LiCl, may deplete the GBM stem cell reservoir independently of CD133 status.
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影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
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120.1
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