EphA2-to-YAP pathway drives gastric cancer growth and therapy resistance
EphA2-to-YAP pathway drives gastric cancer growth and therapy resistance
复制标题
EphA2-to YAP 通路驱动胃癌生长和治疗耐药
DOI：
10.1002/ijc.32609
复制
发表时间：
2019-08-23
影响因子：
6.4
通讯作者：
Chen, Zhikang
中科院分区：
文献类型：
--
作者：
Huang, Changhao;Yuan, Weijie;Chen, Zhikang
Yes-associated protein （YAP）是一种促进细胞增殖、干细胞维持和组织稳态的转录辅激活因子。YAP活性主要通过Hippo途径的丝氨酸/苏氨酸激酶的抑制性磷酸化来调节。在这里，我们发现受体酪氨酸激酶（RTK）产生促红细胞生成素的肝细胞受体A2 （EphA2）与YAP蛋白相互作用并磷酸化，导致胃癌（GC）细胞中YAP的稳定、核易位和激活。EphA2通过增加YAP稳定性和核YAP蛋白诱导化疗耐药。敲低YAP可阻断epha2诱导的胃癌异种移植小鼠模型的肿瘤生长。重要的是，EphA2和YAP的共激活在临床人类胃癌中表现出来，并与胃癌复发有关。因此，我们的研究结果建立了一个新的epha2 - yap通路，该通路驱动GC的生长、进展和治疗耐药，靶向该通路将是治疗GC，特别是化疗耐药GC的有效途径。
Yes-associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin-producing hepatocellular receptor A2 (EphA2) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy-resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2-induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2-to-YAP pathway that drives GC growth, progression and therapy-resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy-resistant GC.