Estradiol-mediated hepatocyte growth factor is involved in the implantation of endometriotic cells via the mesothelial-to-mesenchymal transition in the peritoneum
Estradiol-mediated hepatocyte growth factor is involved in the implantation of endometriotic cells via the mesothelial-to-mesenchymal transition in the peritoneum
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DOI：
10.1152/ajpendo.00573.2014
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发表时间：
2015-06-01
影响因子：
5.1
通讯作者：
Ohmichi, Masahide
中科院分区：
文献类型：
--
作者：
Ono, Yoshihiro J.;Hayashi, Masami;Ohmichi, Masahide
子宫内膜异位症是一种慢性疼痛的妇科疾病，其发病机制是雌激素依赖性的，其特征是子宫内膜组织位于子宫外，经常粘附在腹膜上。然而，子宫内膜异位症的确切病理生理机制仍然难以捉摸。最近的研究表明，人子宫内膜细胞的上皮-间质转化（EMT）对子宫内膜异位症的进展很重要，而另一项先前的研究表明肝细胞生长因子（HGF）与子宫内膜异位症的进展有关。本研究的目的是研究雌二醇在调节HGF产生和腹膜子宫内膜异位症进展中的作用，重点关注腹膜和子宫内膜异位症细胞之间的相互作用。因此，研究发现雌二醇通过上调HGF促进永生化人子宫内膜上皮细胞（hEECs）的增殖、侵袭和迁移，并且在染色质免疫沉淀（ChIP）实验中证实了雌二醇诱导的雌激素受体- α与HGF启动子的直接结合。雌二醇也通过促进HGF的产生诱导heec的EMT。此外，在雌二醇刺激的hEEC条件培养基中，人间皮细胞经历了间皮到间质转化（MMT）。重要的是，雌二醇本身并不诱导MMT，而在HGF抗体存在的情况下，雌二醇刺激的heec条件培养基逆转了MMT过程。这些使用永生化hEECs获得的结果表明，雌二醇诱导的HGF的产生可能在人子宫内膜异位症细胞的腹膜植入中发挥关键作用，通过hEECs的EMT发挥增殖和侵袭作用，促进间皮细胞的MMT。
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-alpha 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.