Wnt/β-catenin通路介导Hippo/YAP信号调控脑胶质瘤生长的研究

Hippo/YAP与Wnt/β-catenin均是肿瘤发生发展中的重要信号通路，研究发现胞浆中的YAP抑制Wnt/β-catenin通路的活性。然而，我们发现胞浆内YAP水平增加，β-catenin的水平与活性也增加，反之亦然，提示Hippo/YAP对Wnt/β-catenin通路存在其他尚未发现的调节机制。根据一系列预实验结果，我们提出‘胞浆内YAP通过抑制APC/Axin/GSK3β破坏复合体活性，和/或与β-catenin竞争结合泛素连接酶β-trCP，提高β-catenin水平与Wnt/β-catenin通路活性’的假说。本项目拟采用培养的细胞、裸鼠肿瘤模型与脑胶质瘤标本，研究YAP 激活Wnt/β-catenin通路促进脑胶质瘤生长的新机制，拓展对两条通路间对话关系的认识，找到联系两个信号通路的关键节点，为设计靶向这两个通路的分子药物及脑胶质瘤的分子靶向治疗提供理论依据。

Hippo/YAP and Wnt/β-catenin are two important signaling pathways in tumorogenesis and it is reported that cytosol YAP inhibits Wnt/β-catenin activity. However, we found that increased YAP in cytoplasma enhanced β-catenin level and activity, while downregulation of YAP decreased β-catenin level and activity, suggesting that there are other unknown mechanism that Hippo/YAP regulates Wnt/β-catenin signaling. Thus, we propose the possible mechanism that cytosol YAP regulates β-catenin level and Wnt/β-catenin activity by inhibiting APC/Axin/GSK3β complex activity and/or competing with β-catenin for forming complex with β-trCP and then degradation. By using the glioma specimens, cultured glioma cells and nude mice, we aimed to explore the role of Hippo/YAP in gliomagenesis and its related mechanism. Our results will extend the knowledge of cross-talk of Hippo/YAP with Wnt/β-catenin pathway,which will provide valuable idea for finding the key joint between Hippo/YAP and Wnt/β-catenin pathways and designing small molecules targeting these two pathways for brain glioma therapy.