ANXA1 Binds and Stabilizes EphA2 to Promote Nasopharyngeal Carcinoma Growth and Metastasis.

Autor:	Feng J; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China.; Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, China., Lu SS; Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, China., Xiao T; Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China., Huang W; Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, China., Yi H; Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, China., Zhu W; Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, China., Fan S; Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, China., Feng XP; Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, China., Li JY; Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, China., Yu ZZ; Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, China., Gao S; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China., Nie GH; Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, China., Tang YY; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China., Xiao ZQ; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China. zhiqiangxiao@csu.edu.cn.; Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, China.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Oct 15; Vol. 80 (20), pp. 4386-4398. Date of Electronic Publication: 2020 Jul 31.
DOI:	10.1158/0008-5472.CAN-20-0560
Abstrakt:	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. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4386/F1.large.jpg. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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