ANXA1 Binds and Stabilizes EphA2 to Promote Nasopharyngeal Carcinoma Growth and Metastasis
ANXA1 Binds and Stabilizes EphA2 to Promote Nasopharyngeal Carcinoma Growth and Metastasis
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ANXA1结合并稳定EphA2促进鼻咽癌生长和转移
DOI：
10.1158/0008-5472.can-20-0560
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发表时间：
2020-10-15
期刊：
影响因子：
11.2
通讯作者：
Xiao, Zhi-Qiang
中科院分区：
文献类型：
--
作者：
Feng, Juan;Lu, Shan-Shan;Xiao, Zhi-Qiang
ANXA1 和 EphA2 的过度表达与多种癌症有关，这两种蛋白在新型抗癌药物的开发中引起了广泛关注。在这里，我们报道ANXA1与Cbl竞争结合EphA2，并通过抑制Cbl介导的EphA2泛素化和鼻咽癌（NPC）降解来增加其稳定性。 ANXA1 与 EphA2 的结合通过提高 EphA2 水平和增加 EphA2 致癌信号传导 (pS897-EphA2) 的活性，促进体外和体内 NPC 细胞的生长和转移。 ANXA1和EphA2的表达呈正相关，且两者在鼻咽癌组织中的表达均显着高于正常鼻咽上皮组织。与仅高表达一种蛋白的患者相比，同时高表达两种蛋白的患者的无病生存期和总生存期较差。此外，ANXA1 N-末端的氨基酸残基20-30aa和28-30aa结合EphA2。基于该N端区域开发了11个氨基酸长的ANXA1衍生肽（EYVQTVKSSKG），该肽破坏了ANXA1与EphA2的连接，成功下调EphA2表达并在体外和小鼠体内显着抑制NPC细胞致癌性。这些发现表明，ANXA1 通过结合和稳定 EphA2 促进 NPC 生长和转移，并提出了一种针对 EphA2 降解和用肽治疗 NPC 的策略。这种治疗策略也可以扩展到两种蛋白高表达的其他癌症。意义：这些发现表明，EphA2 是 NPC 治疗的潜在靶标，并且 ANXA1 衍生肽可抑制 NPC 生长和转移。
Overexpression of ANXA1 and EphA2 has been linked to various cancers and both proteins have attracted considerable attention for the development of new anticancer drugs. Here we report that ANXA1 competes with Cbl for binding EphA2 and increases its stability by inhibiting Cbl-mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC). Binding of ANXA1 to EphA2 promoted NPC cell growth and metastasis in vitro and in vivo by elevating EphA2 levels and increasing activity of EphA2 oncogenic signaling (pS897-EphA2). Expression of ANXA1 and EphA2 was positively correlated and both were significantly higher in NPC tissues than in the normal nasopharyngeal epithelial tissues. Patients with high expression of both proteins presented poorer disease-free survival and overall survival relative to patients with high expression of one protein alone. Furthermore, amino acid residues 20-30aa and 28-30aa of the ANXA1 N-terminus bound EphA2. An 11 amino acid-long ANXA1-derived peptide (EYVQTVKSSKG) was developed on the basis of this N-terminal region, which disrupted the connection of ANXA1 with EphA2, successfully downregulating EphA2 expression and dramatically suppressing NPC cell oncogenicity in vitro and in mice. These findings suggest that ANXA1 promotes NPC growth and metastasis via binding and stabilization of EphA2 and present a strategy for targeting EphA2 degradation and treating NPC with a peptide. This therapeutic strategy may also be extended to other cancers with high expression of both proteins.Significance: These findings show that EphA2 is a potential target for NPC therapeutics and an ANXA1-derived peptide suppresses NPC growth and metastasis.