Abstract：
The most widely accepted hypothesis for the development of glioblastoma suggests that glioblastoma stem-like cells (GSCs) are crucially involved in tumor initiation and recurrence as well as in the occurrence of chemo- and radio-resistance. Mesenchyme homeobox 2 (MEOX2) is a transcription factor overexpressed in glioblastoma, whose expression is negatively correlated with patient survival. Starting from our observation that MEOX2 expression is strongly enhanced in six GSC lines, we performed shRNA-mediated knock-down experiments in two different GSC lines and found that MEOX2 depletion resulted in the inhibition of cell growth and sphere-forming ability and an increase in apoptotic cell death. By a deep transcriptome analysis, we identified a core group of genes modulated in response to MEOX2 knock-down. Among these genes, the repressed ones are largely enriched in genes involved in the hypoxic response and glycolytic pathway, two strictly related pathways that contribute to the resistance of high-grade gliomas to therapies. An in silico study of the regulatory regions of genes differentially expressed by MEOX2 knock-down revealed that they mainly consisted of GC-rich regions enriched for Sp1 and Klf4 binding motifs, two main regulators of metabolism in glioblastoma. Our results show, for the first time, the involvement of MEOX2 in the regulation of genes of GSC metabolism, which is essential for the survival and growth of these cells.
摘要：
关于胶质母细胞瘤发展的最广泛接受的假设表明，胶质母细胞瘤干细胞样细胞（GSC）与肿瘤的发生和复发以及化学和放射性抗性的发生至关重要。间充质同源异型盒2（MEOX2）是胶质母细胞瘤中过度表达的转录因子，其表达与患者生存率呈负相关。从我们的观察开始，MEOX2表达在六个GSC细胞系中强烈增强，我们在两个不同的GSC细胞系中进行了shRNA介导的敲减实验,发现MEOX2耗竭导致细胞生长和球体形成能力的抑制以及凋亡性细胞死亡的增加.通过深度转录组分析，我们确定了一组响应MEOX2敲低而被调节的核心基因。在这些基因中,被抑制的基因在很大程度上富含参与缺氧反应和糖酵解途径的基因，导致高级别神经胶质瘤对治疗产生抗性的两条严格相关的途径。通过MEOX2敲低差异表达的基因的调控区的计算机研究表明，它们主要由富含Sp1和Klf4结合基序的富含GC的区域组成，胶质母细胞瘤代谢的两个主要调节因子。我们的结果显示,第一次,MEOX2参与GSC代谢基因的调节，这对这些细胞的存活和生长至关重要。
