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 ␤-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-1␣/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.

MicroRNA-17 downregulates expression of the PTEN gene to promote the occurrence and development of adenomyosis

“…In AM, the invasion and metastastic abilities of endometrial cells are enhanced, which is an important cause of the disease (29). To the best of our knowledge, the present study was the first to investigate whether miR-17 is involved in altering the biological functions of endometrial cells.…”

Role of Annexin A2 in the EGF-induced epithelial-mesenchymal transition in human CaSki cells

“…The mechanisms of E-cadherin loss in malignant cancers include genetic mutation, epigenetic silencing, transcription repression and proteolytic processes (4). Another research group has also demonstrated that upregulation of ANXA2 is accompanied by the EMT process in endometrial cells, and forced expression of ANXA2 may mediate phenotypic mesenchymal-like cellular changes with structural and functional alteration in a β-catenin/TCF signal-associated manner (29). This could be reversed by inhibition of ANXA2 expression, and another study suggested that ANXA2 is closely associated with tumor progression in HeLa cells (30).…”

Pathogenesis and malignant transformation of adenomyosis (Review)

“…The estrogen dependency is often accompanied by the appearance of EMT features, which is a crucial step for the acquisition of invasive properties of endometrial epithelial cells during adenomyosis progression (22). Estrogen enhances endometrial tissue growth, metastasis and angiogenesis in an adenomyosis model via annexin A2 (ANXA2)-induced EMT (23). These data implicate the crucial role of estrogen-induced EMT in the development of adenomyosis (22).…”