ANXA1 Drives Nasopharyngeal Carcinoma Growth and Metastasis by Binding and Stabilizing EphA2 and the Anti-Tumor Effect of ANXA1-Derived Peptide

ANXA1 and EphA2 play a crucial role in cancer. Here, we report that ANXA1 competes with Cbl for binding EphA2 and increases its stability by inhibiting Cbl-mediated EphA2 ubiquitination degradation in nasopharyngeal carcinoma (NPC), leading to the enhanced NPC growth and metastasis in vitro and in vivo . In human NPC, patients with the high expression of both ANXA1 and EphA2 proteins have poorer disease-free survival and overall survival relative to patients with the high expression of one protein alone. Furthermore, based on the N-terminal amino acid 20-30 region of ANXA1 responsible for binding EphA2, we develop an ANXA1-derived peptide, named as A1 (20-30), that cuts its connection with EphA2, successfully downregulates EphA2 and suppresses NPC oncogenicity in vitro and in vivo. These findings reveal that ANXA1, via binding and stabilizing EphA2, drives NPC growth and metastasis, and present a strategy for targeting EphA2 degradation and treating NPC with a peptide.