EphA2‐to‐YAP pathway drives gastric cancer growth and therapy resistance

作者：Changhao Huang, Weijie Yuan, Lai Chen, Shangwei Zhong, Yang Chen, Ran Wang, Linfeng Mao, Zihua Chen, Zhikang Chen · 发表于：International Journal of Cancer · 年份：2019 · DOI：10.1002/ijc.32609 · 被引用次数：85 · 研究领域：Hippo pathway signaling and YAP/TAZ、Axon Guidance and Neuronal Signaling、Hereditary Neurological Disorders

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.