Estradiol-mediated hepatocyte growth factor is involved in the implantation of endometriotic cells via the mesothelial-to-mesenchymal transition in the peritoneum

Abstract

Ono YJ, Hayashi M, Tanabe A, Hayashi A, Kanemura M, Terai Y, Ohmichi M. Estradiol-mediated hepatocyte growth factor is involved in the implantation of endometriotic cells via the mesothelial-to-mesenchymal transition in the peritoneum. Am J Physiol Endocrinol Metab 308: E950 -E959, 2015. First published April 7, 2015 doi:10.1152/ajpendo.00573.2014.-The pathogenesis of endometriosis, a chronic painful gynecological disease characterized by the presence of endometrial tissue located outside of the uterus and often adhering to the peritoneum, is known to be estrogen dependent. However, the precise pathophysiology of endometriosis remains elusive. Recent studies indicate that the epithelial-to-mesenchymal transition (EMT) of human endometrial cells is important for the progression of endometriosis, and another previous study has implicated hepatocyte growth factor (HGF) in endometriosis progression. The aim of the present study was to examine the role of estradiol in the regulation of HGF production and progression of peritoneal endometriosis, focusing on the interactions between the peritoneum and endometriotic cells. Consequently, estradiol was found to promote the proliferation, invasion, and migration of immortalized human endometrial epithelial cells (hEECs) via HGF upregulation, and the estradiol-induced direct binding of estrogen receptor-␣ to the HGF promoter was confirmed on a chromatin immunoprecipitation (ChIP) assay. Estradiol also induced the EMT in hEECs by promoting HGF production. Furthermore, human mesothelial cells underwent the mesothelial-to-mesenchymal transition (MMT) during culture with estradiol-stimulated hEEC conditioned medium. Importantly, estradiol itself did not induce the MMT, and the estradiol-stimulated hEEC-conditioned medium in the presence of HGF antibodies reversed the MMT process. These results, which were obtained using immortalized hEECs, indicate that estradiol-induced HGF production may play a crucial role in the peritoneal implantation of human endometriotic cells by exerting proliferative and invasive effects via the EMT in hEECs and promoting the MMT in mesothelial cells.epithelial-to-mesenchymal transition; endometriosis; estradiol; hepatocyte growth factor; mesothelial-to-mesenchymal transition ENDOMETRIOSIS IS A CHRONIC, BENIGN DISEASE characterized by the presence of endometrium-like tissue outside the uterine cavity primarily on the ovaries or pelvic peritoneum. This condition is a major cause of symptoms, such as pelvic pain, dysmenorrhea, dyspareunia, and infertility, that affect 6 -10% of females of reproductive age and at least one-third of women with infertility and often relapses after surgery (9 -11). Although endometriosis was first described in 1860 (33), the etiology and pathogenesis of this disorder remain unclarified.

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

“…Interestingly, the activation of the Wnt/β-catenin signaling pathway is responsible for EMT induction in endometriosis 21 and adenomyosis 2 . In addition, hepatocyte growth factor (HGF) can induce EMT in endometriosis 14 and adenomyosis 13 . Furthermore, EZH2 was shown to silence miR-34a, leading to activation of the HGF/Met/Snail pathway and subsequent EMT in gastric cancer cells 45 , indicating that EZH2 and other PRC2 components might mediate HGF-induced EMT in endometriosis 13, 14, 19 .…”

“…In addition, hepatocyte growth factor (HGF) can induce EMT in endometriosis 14 and adenomyosis 13 . Furthermore, EZH2 was shown to silence miR-34a, leading to activation of the HGF/Met/Snail pathway and subsequent EMT in gastric cancer cells 45 , indicating that EZH2 and other PRC2 components might mediate HGF-induced EMT in endometriosis 13, 14, 19 . Since EZH2 can epigenetically silence miR-200b 46 , an EMT suppressor in endometriosis 18 , EZH2 possibly promotes EMT in endometriosis through the inhibition of miR-34a and miR-200b expression.…”

“…Indeed, to date several factors have been shown to regulate EMT in endometriosis and adenomyosis, including estrogen 11 , Wnt/β-catenin 2 , lipocalin 2 12 , hepatocyte growth factor (HGF) 2, 13, 14 , lysyl oxidase 15 , periostin 16 , hypoxia 17 , microRNA-200b (miR-200b) 18 , platelets 7 and possibly Myc 19 and LSD1 20 . It becomes clear that EMT not only increases cellular invasiveness but also promotes fibrogenesis 7, 21 .…”

Epithelial-to-mesenchymal transition in the development of endometriosis

“…Firstly, ERα could directly bind to hepatocyte growth factor (HGF) promoter, then induces EMT in the human endometrial epithelial cells [53]. Besides, ERα could also possibly up-regulate of both Snail and Slug through activation of their promoter activities [54].…”

Phytotherapeutische Behandlungsmöglichkeiten bei Endometriose-Erkrankungen

“…Die biochemische Dysbalance führt oft zu Funktionsstö-rungen wie chronischen Schmerzen sowie Tubentransport-und Einnistungsproblemen. Anatomische Strukturveränderungen können, müssen jedoch nicht eine Folge sein [8,19]. Mit meinen Erfahrungen übereinstim-mend, können schon minimale Ände-rungen in der Exposition zu deutlichen Veränderungen in der Endometriose-Aktivität führen [13].…”