2. Academic Validation
  3. EPH receptor A2 governs a feedback loop that activates Wnt/β-catenin signaling in gastric cancer

EPH receptor A2 governs a feedback loop that activates Wnt/β-catenin signaling in gastric cancer

  • Cell Death Dis. 2018 Nov 19;9(12):1146. doi: 10.1038/s41419-018-1164-y.
Qiu Peng 1 2,  Ling Chen 3,  Wei Wu 3,  Jia Wang 2,  Xiang Zheng 2,  Zihua Chen 3,  Qin Jiang 1,  Jiaqi Han 1,  Lingyu Wei 2,  Lujuan Wang 2,  Jin Huang 4,  Jian Ma 5 6 7
Affiliations

Affiliations

  • 1 Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 2 Cancer Research Institute, School of Basic Medical Science, Central South University, Hunan, China.
  • 3 Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Hunan, China.
  • 4 Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
  • 5 Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
  • 6 Cancer Research Institute, School of Basic Medical Science, Central South University, Hunan, China. [email protected].
  • 7 Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Translational Radiation Oncology at Hunan Cancer Hospital, Changsha, Hunan, China. [email protected].
PMID: 30451837 DOI: 10.1038/s41419-018-1164-y
Abstract

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.

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