Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cancer Research Institute, School of Basic Medical Science, Central South University, Hunan, China.
Cell Death Dis. 2018 Nov 19;9(12):1146. doi: 10.1038/s41419-018-1164-y.
The erythropoietin-producing hepatoma (EPH) receptor A2 (EphA2) belongs to the Eph family of receptor tyrosine kinases. EphA2 is highly correlated with the formation of many solid tumors and has been linked to the dysregulation of signaling pathways that promote tumor cell proliferation, migration, and invasion as well as angiogenesis. Deregulation of Wnt signaling is implicated in many forms of human disease including gastric cancer. We previously reported that EphA2 promotes the epithelial-mesenchymal transition through Wnt/β-catenin signaling in gastric cancer. Herein, we present a novel mechanism by which EphA2 regulates Wnt/β-catenin signaling. EphA2 acts as a receptor for Wnt ligands and recruits Axin1 to the plasma membrane by directly binding Dvl2. The EphA2-Dvl2/Axin1 interaction was enhanced by Wnt3a treatment, suggesting that EphA2 acts as a functional receptor for the Wnt/β-catenin pathway and plays a vital role in downstream signaling. We showed that Dvl2 mediates the EphA2-Axin1 interaction by binding to the tyrosine kinase domain of EphA2. We propose that EphA2/Dvl2/Axin1 forms a complex that destabilizes the β-catenin destruction complex and allows β-catenin to translocate to the nucleus and initiate the transcription of c-MYC, the primary Wnt signaling target gene. Intriguingly, c-MYC could bind directly to the EphA2 and Wnt1 promoter to enhance their transcription. The entire process formed an EphA2-mediated feed-forward loop. A small molecular inhibitor of EphA2 potently inhibited the proliferation of gastric cancer in vitro and in vivo, including gastric cancer patient-derived xenografts. Thus, our data identify EphA2 as an excellent candidate for gastric cancer therapy.
促红细胞生成素产生的肝癌（EPH）受体 A2（EphA2）属于受体酪氨酸激酶 Eph 家族。EphA2 与许多实体瘤的形成高度相关，并与促进肿瘤细胞增殖、迁移和侵袭以及血管生成的信号通路失调有关。Wnt 信号的失调与包括胃癌在内的许多形式的人类疾病有关。我们之前报道 EphA2 通过 Wnt/β-catenin 信号促进胃癌的上皮-间充质转化。在此，我们提出了 EphA2 调节 Wnt/β-catenin 信号的新机制。EphA2 作为 Wnt 配体的受体，通过直接与 Dvl2 结合将 Axin1 募集到质膜。EphA2-Dvl2/Axin1 相互作用在 Wnt3a 处理下增强，表明 EphA2 作为 Wnt/β-catenin 通路的功能性受体发挥作用，并在下游信号转导中发挥重要作用。我们表明 Dvl2 通过与 EphA2 的酪氨酸激酶结构域结合来介导 EphA2-Axin1 相互作用。我们提出 EphA2/Dvl2/Axin1 形成一个复合物，破坏 β-catenin 破坏复合物，允许 β-catenin 易位到核内并启动 Wnt 信号的主要靶基因 c-MYC 的转录。有趣的是，c-MYC 可以直接与 EphA2 和 Wnt1 启动子结合，增强它们的转录。整个过程形成 EphA2 介导的正反馈环。EphA2 的小分子抑制剂在体外和体内均能有效抑制胃癌的增殖，包括胃癌患者来源的异种移植物。因此，我们的数据将 EphA2 鉴定为胃癌治疗的优秀候选药物。
