title: Proteomics identification of annexin A2 as a key mediator in the metastasis and proangiogenesis of endometrial cells in human adenomyosis.
abstract: Adenomyosis is a common estrogen-dependent disorder of females characterized by a downward extension of the endometrium into the uterine myometrium and neovascularization in ectopic lesions. It accounts for chronic pelvic pain, dysmenorrhea, menorrhagia, and infertility in 8.8-61.5% women worldwide. However, the molecular mechanisms for adenomyosis development remain poorly elucidated. Here, we utilized a two-dimensional polyacrylamide gel electrophoresis/MS-based proteomics analysis to compare and identify differentially expressed proteins in matched ectopic and eutopic endometrium of adenomyosis patients. A total of 93 significantly altered proteins were identified by tandem MS analysis. Further cluster analysis revealed a group of estrogen-responsive proteins as dysregulated in adenomyosis, among which annexin A2, a member of annexin family proteins, was found up-regulated most significantly in the ectopic endometrium of adenomyosis compared with its eutopic counterpart. Overexpression of ANXA2 was validated in ectopic lesions of human adenomyosis and was found to be tightly correlated with markers of epithelial to mesenchymal transition and dysmenorrhea severity of adenomyosis patients. Functional analysis demonstrated that estrogen could remarkably up-regulate ANXA2 and induce epithelial to mesenchymal transition in an in vitro adenomyosis model. Enforced expression of ANXA2 could mediate phenotypic mesenchymal-like cellular changes, with structural and functional alterations in a β-catenin/T-cell factor (Tcf) signaling-associated manner, which could be reversed by inhibition of ANXA2 expression. We also proved that enforced expression of ANXA2 enhanced the proangiogenic capacity of adenomyotic endometrial cells through HIF-1α/VEGF-A pathway. In vivo, we demonstrated that ANXA2 inhibition abrogated endometrial tissue growth, metastasis, and angiogenesis in an adenomyosis nude mice model and significantly alleviated hyperalgesia. Taken together, our data unraveled a dual role for ANXA2 in the pathogenesis of human adenomyosis through conferring endometrial cells both metastatic potential and proangiogenic capacity, which could serve as a potential therapeutic target for the treatment of adenomyosis patients.
authors.affiliation: Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Shengtao
authors.initials: S
authors.lastname: Zhou
authors.forename: Tao
authors.initials: T
authors.lastname: Yi
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Ce
authors.initials: C
authors.lastname: Bian
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Qi
authors.forename: Xiang
authors.initials: X
authors.lastname: He
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.forename: Jingyi
authors.initials: J
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000328:Adult; D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism*; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D005810:Multigene Family; D009215:Myometrium / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D040901:Proteomics; D053719:Tandem Mass Spectrometry; D014594:Uterine Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A