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

Yoshihiro J Ono, Yoshihiro Joshua Ono, Masami Hayashi, Akiko Tanabe, Atsushi Hayashi, Masanori Kanemura, Yoshito Terai, Masahide Ohmichi
American journal of physiology. Endocrinology and metabolism · 2015 · vol. 308(11) , pp. E950–E959 · doi:10.1152/ajpendo.00573.2014 · PMID:25852006 · W1982172605
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Estradiol upregulates hepatocyte growth factor to promote endometriotic cell proliferation, invasion, and migration via epithelial-to-mesenchymal transition, and induces peritoneal mesothelial-to-mesenchymal transition, facilitating endometriosis implantation.

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Abstract

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-α 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.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Epithelial-Mesenchymal Transition Estradiol Hepatocyte Growth Factor Peritoneal Diseases Peritoneum Adult Case-Control Studies Cell Adhesion Cell Adhesion Cell Adhesion Cell Proliferation Cell Proliferation Cell Proliferation Cells, Cultured Cross-Sectional Studies Endometriosis Endometriosis Endometriosis Epithelial-Mesenchymal Transition

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