PDCD10调控EphB4信号通路在胶质母细胞瘤侵袭中的作用及机制研究

Glioblastoma (GBM) is the most common malignant tumor in central nervous system. Accumulative studies elucidated that the tumor invasion of GBM was associated with tumor recurrence and poor prognosis. Tumor cell proliferation and migration are key processes during tumor invasion. Other groups and ours demonstrated that Programmed Cell Death 10 (PDCD10) was involved in the regulation of cell proliferation and migration. Recently, the downregulation of PDCD10 was discovered in GBM tissue. Our study found that the downregulation of PDCD10 in GBM cells promoted tumor cell proliferation and migration. Consequently, we raised our hypothesis that PDCD10 might regulate GBM invasion. Further study found that EphB4 might be the target of PDCD10 in GBM. In addition, the EphB4 signaling pathway was demonstrated in the regulation of GBM invasion. Therefore, the present project is to explore that the impact of PDCD10 in GBM tumor behaviors in vitro and in vivo, and to address the potential mechanism of PDCD10 regulating EphB4 signaling pathway and its role in GBM invasion at both molecular and functional levels. This novel study may provide the evidence for defining PDCD10 as new target in GBM therapy.

胶质母细胞瘤（GBM）是中枢神经系统最常见的恶性肿瘤。局部脑实质侵袭是GBM的重要特征，是肿瘤无法手术根除，导致复发和影响预后的关键因素。肿瘤细胞增殖和迁移是调控肿瘤侵袭的关键步骤。国内外研究组和我们研究都证实程序性细胞凋亡因子10（PDCD10）参与调控细胞增殖和迁移。最近研究报道GBM组织中PDCD10表达降低。我们实验发现下调PDCD10显著促进GBM细胞增殖和迁移。因此我们推测PDCD10可能参与调控GBM侵袭，深入研究其调控机制具有重要意义。利用蛋白芯片筛选我们发现EphB4可能是PDCD10作用的靶点。结合文献报道EphB4参与调控包括GBM在内的多种肿瘤侵袭。基于此，本项目以人脑GBM组织，体外细胞和体内动物模型为实验对象，采用分子生物学和药物干预等手段，探索下调PDCD10调控EphB4信号通路在GBM侵袭中的作用及分子机制，为以PDCD10为新靶标治疗GBM提供理论依据。

胶质母细胞瘤（GBM）是中枢神经系统最常见的恶性肿瘤。局部脑实质侵袭是GBM的重要特征，是肿瘤无法手术根除，导致复发和影响预后的关键因素。肿瘤细胞增殖和迁移是调控肿瘤侵袭的关键步骤。本课题在收集和检测人脑GBM标本的基础上发现PDCD10与EphB4表达的相关性，以及与患者不良预后的关系；在体外构建了稳定下调和过表达PDCD10的胶质瘤细胞系（U251和U373），证实了PDCD10介导EphB4受体内吞，调控EphB4信号途径进而促进肿瘤迁移和侵袭的分子机制；裸鼠原位GBM肿瘤模型验证了PDCD10体内促进移植瘤生长。综上所述，本课题从GBM患者，体外细胞和体内动物模型三方面阐述了PDCD10促进GBM迁移和侵袭的作用和介导EphB4信号通路的机制。本课题的研究结果为研发PDCD10的检测试剂盒，以及靶向PDCD10的药物治疗GBM提供了理论依据。