USP10介导WT1去泛素化修饰在胶质瘤干细胞间质特性维持中的作用及机制研究

胶质瘤干细胞(GSC)是启动胶质瘤发生发展的“种子”细胞，依据生物学特征不同分为两种亚型，即前神经元型(PN)和间质型(MES)。与PN GSC相比，MES GSC具有更强的侵袭性和致瘤性。最近研究表明，Wilms肿瘤基因1(WT1)在MES GSC中异常高表达，但具体调控机制不详。我们前期研究证实，WT1是一个易降解蛋白，通过高通量筛选发现去泛素化酶USP10可能在维持WT1蛋白稳态中发挥作用。据此，我们提出假说，USP10-WT1信号轴可能是维持GSC间质特性的关键通路。为验证这一假说，我们将通过两种亚型GSC、裸鼠颅内移植瘤模型以及患者肿瘤组织，从分子、细胞、动物以及临床样本等多层次探讨USP10-WT1信号轴在维持GSC间质特性中的作用，明确USP10小分子抑制剂的抗肿瘤疗效。本项目对阐明GSC间质特性维持机理具有重要意义，为胶质瘤的分子靶向治疗提供新的靶点和理论依据。

Glioma stem cells (GSCs) are thought to be the "seed" cells that initiate the development of glioma. Previous studies have identified two mutually-exclusive GSC subtypes with distinct biological behaviors, proneural (PN) and mesenchymal (MES) GSCs. As compared with PN GSCs, MES GSCs are more aggressive and tumorigenic. Recent studies have shown that Wilms tumor gene 1 (WT1) is preferentially expressed in MES GSCs, but not in PN GSCs. However, the molecular mechanism underlying WT1 dysregulation remains unclear. In our preliminary experiments, we found that WT1 is an easily degradable protein. Moreover, we conducted a large-scale siRNA screening to identify WT1-interacting deubiquitylases. The results of our screen and functional validation reveal that USP10 might be responsible for WT1 protein stability. Thus, we propose a possible scenario whereby USP10 could mediate the stabilization of WT1, which maintains mesenchymal traits of GSCs. To test this hypothesis, we seek to investigate the effects of USP10-WT1 axis on the maintenance of stemness and tumorigenic potential of GSCs, and tested the efficacy of USP10-specific small molecule inhibitors using preclinical models of GSC-derived xenografts. This subject is of great significance for elucidating the mechanism how GSCs maintains their MES identity and provides a theoretical basis for clinical molecular targeted treatment of glioma.