title: Involvement of hepatocyte growth factor-induced epithelial-mesenchymal transition in human adenomyosis.
abstract: Adenomyosis is commonly believed to arise from the basalis endometrium. As an estromedin growth factor, hepatocyte growth factor (HGF) exhibits multiple functions in endometriosis, a disease commonly believed to arise from the functionalis endometrium. Here, we investigated the role of HGF in the occurrence of epithelial-mesenchymal transition (EMT) in adenomyosis. Full-thickness-biopsy specimens from endometrium to myometrium were collected after hysterectomy from women with and without adenomyosis. The relationship between HGF and E-cadherin (epithelial cell marker) and N-cadherin (mesenchymal cell markers) was examined at the gene and protein levels using endometrial epithelial cells (EECs) in culture and tissues by quantitative RT-PCR and immunohistochemistry. The gene and protein expressions of two transcriptional repressors of E-cadherin, SLUG and SNAIL, were examined using Ishikawa cells and in response to HGF and estrogen (E2). HGF down-regulated E-cadherin and up-regulated N-cadherin mRNA expression in EECs, and an inverse relationship in protein expression between HGF and E-cadherin was observed in basalis endometria derived from women with diffuse and focal adenomyosis. HGF induced morphological changes of EECs from a cobblestone-like appearance to spindle-shaped cells and promoted migration of EECs. Ishikawa cells exhibited up-regulation of SLUG/SNAIL gene expression in response to both HGF and E2 with an additive effect between them. HGF- and E2-promoted SLUG/SNAIL gene expression was significantly abrogated after pretreatment of cells with anti-HGF antibody or ICI 182720, an estrogen receptor antagonist. HGF may be involved in gland invagination deep into the myometrium by inducing EMT at the endo-myometrial junction in women with adenomyosis.
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan nemokhan@nagasaki-u.ac.jp.
authors.forename: Khaleque Newaz
authors.initials: KN
authors.lastname: Khan
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Kitajima
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hiraki
authors.affiliation: Saiseikai Nagasaki Hospital, Nagasaki, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fujishita
authors.affiliation: Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Masuzaki
mesh_terms: D062788:Adenomyosis / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D048430:Cell Shape / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008875:Middle Aged; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015820:Cadherins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor
keywords: EMT; HGF; adenomyosis; basalis endometrium; estrogen