title: Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis.
abstract: Adenomyosis is an oestrogen-dependent disease caused by a downward extension of the endometrium into the uterine myometrium. Epithelial-mesenchymal transition (EMT) endows cells with migratory and invasive properties and can be induced by oestrogen. We hypothesized that oestrogen-induced EMT is critical in the pathogenesis of adenomyosis. We first investigated whether EMT occurred in adenomyotic lesions and whether it correlated with serum 17β-oestradiol (E2) levels. Immunohistochemistry was performed on adenomyotic lesions and corresponding eutopic endometrium samples from women with adenomyosis. Endometria from women without endometrial disorders were used as a control. In the epithelial component of adenomyotic lesions, vimentin expression was up-regulated and E-cadherin expression was down-regulated compared to the eutopic endometrium, suggesting that EMT occurs in adenomyosis. In adenomyosis, the serum E2 level was negatively correlated with E-cadherin expression in the epithelial components of the eutopic endometrium and adenomyotic lesions, suggesting the involvement of oestrogen-induced EMT in endometrial cells. In oestrogen receptor-positive Ishikawa endometrial epithelial cells, oestrogen induced a morphological change to a fibroblast-like phenotype, a shift from epithelial marker expression to mesenchymal marker expression, increased migration and invasion, and up-regulation of the EMT regulator Slug. Raloxifene, a selective oestrogen receptor modulator, abrogated these effects. To determine the role of oestrogen-induced EMT in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium or adenomyotic lesions from adenomyosis patients into ovariectomized SCID mice. The implantation of endometrium was oestrogen-dependent and was suppressed by raloxifene. Collectively, these data highlight the crucial role of oestrogen-induced EMT in the development of adenomyosis and suggest that raloxifene may be a potential therapeutic agent for adenomyosis patients.
authors.affiliation: Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
authors.forename: Hsin-Yang
authors.initials: HY
authors.lastname: Li
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.forename: Nae-Fang
authors.initials: NF
authors.lastname: Twu
authors.forename: Ming-Shyen
authors.initials: MS
authors.lastname: Yen
authors.forename: Peng-Hui
authors.initials: PH
authors.lastname: Wang
authors.forename: Teh-Ying
authors.initials: TY
authors.lastname: Chou
authors.forename: Yen-Ni
authors.initials: YN
authors.lastname: Liu
authors.forename: Kuan-Chong
authors.initials: KC
authors.lastname: Chao
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation; D004715:Endometriosis / Q000378:metabolism / Q000473:pathology*; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D004847:Epithelial Cells / Q000473:pathology; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D008598:Menstruation / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D015820:Cadherins; D004967:Estrogens; C000604407:SNAI1 protein, human; D020845:Selective Estrogen Receptor Modulators; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D020849:Raloxifene Hydrochloride; D004958:Estradiol