ZEB1 regulates glioma stemness through LIF repression.
ZEB1 regulates glioma stemness through LIF repression.
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DOI：
10.1038/s41598-017-00106-x
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发表时间：
2017-02-28
影响因子：
4.6
通讯作者：
Yu JS
中科院分区：
文献类型：
--
作者：
Edwards LA;Li A;Berel D;Madany M;Kim NH;Liu M;Hymowitz M;Uy B;Jung R;Xu M;Black KL;Rentsendorj A;Fan X;Zhang W;Yu JS
胶质瘤中异常表达的干细胞调节基因的鉴定将增加对胶质瘤肿瘤干细胞（GCSC）在胶质瘤毒力中作用的理解。通过对超过4000例脑癌的基因组进行研究，我们发现约15%（II级和III级）和50%的胶质母细胞瘤中存在ZEB 1缺失。对2,988例胶质瘤患者的ZEB 1拷贝数状态进行的荟萃分析显示，破坏性ZEB 1缺失与生存率降低相关。我们确定了ZEB 1的LIF（干性因子）启动子区域内的结合位点，并证明LIF抑制ZEB 1。GCSC中的ZEB 1敲低引起与GCSC自我更新和分化抑制相称的LIF诱导。IFN-γ处理GCSC诱导ZEB 1表达，减弱LIF活性。这些发现暗示ZEB 1作为胶质瘤中的干细胞调节因子，当其缺失时导致干细胞性、致瘤性增加和患者生存期缩短。
The identification of a stem cell regulatory gene which is aberrantly expressed in glioma and associated with patient survival would increase the understanding of the role of glioma cancer stem cells (GCSCs) in the virulence of gliomas. Interrogating the genomes of over 4000 brain cancers we identified ZEB1 deletion in ~15% (grade II and III) and 50% of glioblastomas. Meta-analysis of ZEB1 copy number status in 2,988 cases of glioma revealed disruptive ZEB1 deletions associated with decreased survival. We identified ZEB1 binding sites within the LIF (stemness factor) promoter region, and demonstrate LIF repression by ZEB1. ZEB1 knockdown in GCSCs caused LIF induction commensurate with GCSC self-renewal and inhibition of differentiation. IFN-γ treatment to GCSCs induced ZEB1 expression, attenuating LIF activities. These findings implicate ZEB1 as a stem cell regulator in glioma which when deleted leads to increased stemness, tumorigenicity and shortened patient survival.