TBX1作为转录因子调控多种成体干细胞的生物学功能,并参与机体的生长发育。然而，对于TBX1表达调控机制及其在肿瘤干细胞中的功能角色还鲜有报道。本课题组在前期研究中发现，胶质瘤干细胞中TBX1启动子区域呈异常低甲基化状态的同时TBX1的表达水平明显增高，而沉默TBX1后胶质瘤干细胞的干性特征显著减弱。基于此，我们推测在胶质瘤干细胞中TBX1启动子区域低甲基化可能促进TBX1表达上调，继而有助于胶质瘤干细胞功能特征的维持。因此，本课题拟采用免疫组化、RNAi等方法：1）在细胞、整体动物和组织水平研究TBX1启动子甲基化状态对TBX1表达调控的影响，并探索TBX1在胶质瘤干细胞干性特征维持中的功能角色，为靶向肿瘤干细胞的治疗策略提供明确的切入点和特异靶标；2）在细胞和组织水平探究TBX1启动子甲基化调控TBX1表达及TBX1参与肿瘤细胞干性维持的分子机制，以期深入认知恶性肿瘤发生发展的本质。

TBX1, as a transcription factor，excute important biological function in the regulation of embryonic and normal stem cell.However, it is not well known that the regulation mechanisms of TBX and its role in cancer stem cell(CSCs).In our previous study, we found that the TBX1 hypomethylation was observed in glioma cancer stem cells(GSCs),along with TBX1 overexpression. When we reduced Tbx1 mRNA and protein levels using an RNAi knock-down approach in GSCs,the stemness dispeared.Based on the above results,we hypothesized the promotor hypomethyletion could promote TBX1 expression and further make it maintain the stemness of GSCs. Therefore, this project intends to use immunohistochemistry, RNAi and other methods: 1) To research the effect of promoter aberrant methylation on the expression of TBX1, and investigate the role of TBX1 in stemness maintenance of GSCs in different levels, to provide specific entrance and markers targeted glioma cancer stem cells in cancer treatments; 2) To study the detail regulation mechanisms of promoter methylation on TBX1 and molecular mechanisms of TBX1 in maintaining cancer stem cells, to understand the essence of the development and progression of malignant tumor.

TBX1，是T-box转录因子家族中重要的转录因子，调控胚胎发育及多种成体干细胞的生物学功能。我们在研究中发现，胶质瘤干细胞中TBX1表达水平明显增高；过表达或沉默TBX1后，胶质瘤干细胞的自我更新和增殖能力分别明显增强和降低，与此同时，干性转录因子SOX2,OCT4 和 Nanog 的表达也相应增高或者降低。在临床样本中，我们发现TBX1与胶质瘤干细胞marker CD133共表达，且TBX1的表达与患者肿瘤大小和预后呈正相关。另外，机制研究提示TBX1启动子甲基化状态可以在转录水平调控TBX1的表达。这些结果表明了DNA低甲基化是调节TBX1表达的重要机制，而TBX1在维持胶质瘤干细胞特性中的发挥重要作用，为以肿瘤干细胞作为胶质瘤的靶向治疗提供了理论依据。