Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
Sci Rep. 2017 Feb 28;7(1):69. doi: 10.1038/s41598-017-00106-x.
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.
鉴定出在神经胶质瘤中异常表达并与患者生存相关的干细胞调控基因，将有助于增加对神经胶质瘤癌症干细胞（GCSC）在神经胶质瘤侵袭性中的作用的理解。通过对超过 4000 例脑癌的基因组进行分析，我们发现 ZEB1 缺失存在于约 15%（II 级和 III 级）和 50%的神经胶质瘤中。对 2988 例神经胶质瘤中 ZEB1 拷贝数状态的荟萃分析显示，破坏 ZEB1 缺失与降低的生存率相关。我们在 LIF（干性因子）启动子区域内鉴定出 ZEB1 结合位点，并证明 ZEB1 可抑制 LIF。在 GCSC 中敲低 ZEB1 导致 LIF 诱导，与 GCSC 自我更新和分化抑制相一致。IFN-γ 处理 GCSC 诱导 ZEB1 表达，减弱 LIF 活性。这些发现表明 ZEB1 是神经胶质瘤中的一种干细胞调控因子，当缺失时会导致干性增加、肿瘤发生和患者生存时间缩短。
