抑制ANXA1与EphA2蛋白互作的多肽抗鼻咽癌的作用及其机制研究

我们前期研究发现，ANXA1与EphA2蛋白互作通过增加EphA2的稳定性促进鼻咽癌的生长和转移，ANXA1氨基末端11个氨基酸衍生肽—A11与靶蛋白EphA2结合，促进EphA2泛素化降解，抑制鼻咽癌细胞体外增殖、移动和侵袭，但A11抗鼻咽癌作用及其机制需要进一步阐明。为此，项目拟开展A11多肽抑制ANXA1与EphA2互作抗鼻咽癌的作用及其机制研究：分析A11是否通过干扰ANXA1与EphA2互作，促进Cbl介导的EphA2泛素化降解；分析A11是否通过下调EphA2的表达，抑制EphA2关键促瘤信号通路的活性发挥抗鼻咽癌作用；优化A11的结构和效能，提高A11与靶蛋白EphA2的亲和性、增加A11稳定性；分析A11对小鼠的毒副作用，初步确定A11的安全性。项目研究成果不仅可揭示A11抗鼻咽癌的作用及其机制，而且能为鼻咽癌治疗提供一种潜在的治疗性多肽，具有重要的科学意义及临床转化价值。

Our recent study discovered that the interaction of ANXA1 and EphA2 promotes nasopharyngeal carcinoma (NPC) growth and metastasis, and the eleven-amino acid long peptide derived from ANXA1 N terminal, named as A11, binds to the targeted protein EphA2 and increases its ubiquitination degradation, and inhibits the in vitro NPC cell proliferation, migration and invasion. But the anti-NPC effect and mechanism of A11 need to further be elucidated. In this project, we will investigate the anti-NPC effect and mechanism of A11 by inhibiting ANXA1and EphA2 interaction, and the main investigating contents are as the followings: (1) analyzing whether A11 increases Cbl-mediated ubiquitination degradation of EphA2 by disturbing the interaction of ANXA1 and EphA2; (2) analyzing whether A11 inhibits NPC growth and metastasis by degrading EphA2 and inhibiting the activity of EphA2 key oncogenic signaling pathway; (3) optimizing the structure and activity of A11 to increase the ability of A11 binding to EphA2 and A11 stability; (4) analyzing the toxic side effects of A11 in mice to evaluate its in vivo safety. Our expected results will not only be helpful to reveal the role and mechanism of A11 anti-NPC effects, but also provide a potential therapeutic peptide for treating NPC, which has important scientific significance and clinical translational value.