YAP1通过TNKS2和Dvl2调控Wnt/β-catenin活性促进胃癌发生发展的研究

Hippo-YAP是驱动胃癌发生发展的重要的信号通路，高水平YAP1/TAZ是维持胃癌细胞恶性表型的重要基础。而YAP1对Wnt/β-catenin的调控机制尚待深入研究。β-catenin是Wnt信号的枢纽，与胃癌的发生发展密切相关。研究显示Wnt和Hippo信号通路存在相互调控的作用。申请人前期研究发现YAP1能正向调控Dvl2和TNKS2分子，而TNKS2和Dvl2能够促进β-catenin入核。因此，本课题提出“YAP1通过TNKS2和Dvl2调控Wnt/β-catenin的活性进而促进胃癌发生发展"的科学假设。基于上述背景，我们拟从细胞功能、分子机制、在体实验和临床相关性四个层次，阐明YAP1和Wnt/β-catenin之间的相互调节机制及其对胃癌发生发展的影响。本研究将为解析胃癌发生发展进程中信号通路互作的网络提供重要实验依据，为胃癌预后评价指标提供有价值的理论依据。

Hippo-YAP signaling pathway is a vital signaling pathway driving the occurrence and development of gastric cancer. High expression level of YAP1/TAZ is an important biomarker for maintaining the malignant phenotype of gastric cancer cells. But the mechanism of regulation of YAP1 promoting Wnt signaling pathway is still elusive. β-Catenin is the key downstream of Wnt signaling pathway, which is closely related to the occurrence and development of gastric cancer. Researches have shown that Wnt and Hippo signaling pathways have crosstalk with each other. Our studies found that YAP1 can positively regulate DVL2 and TNKS2, which can promote β-catenin translocating to nucleus. Therefore, we propose a scientific hypothesis that YAP1 regulates Wnt/β-catenin signaling pathway through DVL2 and TNKS2 for promoting the occurrence and development of gastric cancer. Based on these, we intend to clarify the regulatory mechanism between YAP1 and Wnt/β-Catenin and its effect on the occurrence and development of gastric cancer from four levels of cell function, molecular mechanism, in vivo experiment and clinical correlation. This study will provide an important experimental basis for the analysis of the interaction network of signaling pathways in gastric cancer, and provide a valuable theoretical basis for the prognostic indicators of gastric cancer.