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Alterations of endometrial epithelial-mesenchymal transition and MAPK signaling components in women with PCOS are partially modulated by metformin in vitro.

Journal article
Authors Min Hu
Yuehui Zhang
Xin Li
Peng Cui
Juan Li
Mats Brännström
Linus Ruijin Shao
Håkan Billig
Published in Molecular human reproduction
Volume 26
Issue 5
Pages 312-326
ISSN 1460-2407
Publication year 2020
Published at Institute of Clinical Sciences, Department of Surgery
Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Physiology
Institute of Clinical Sciences, Department of Obstetrics and Gynecology
Institute of Clinical Sciences
Pages 312-326
Language en
Keywords Endometrial hyperplasia, epithelial-mesenchymal transition, MAPK, PCOS,
Subject categories Obstetrics, Gynecology and Reproductive Medicine, Endocrinology and Diabetes


Growing evidence suggests that epithelial-mesenchymal transition (EMT) and its regulator mitogen-activated protein kinase (MAPK) contribute to endometria-related reproductive disorders. However, the regulation of EMT and MAPK signaling components in the endometrium from polycystic ovary syndrome (PCOS) patients has not been systematically investigated and remains elusive. In humans, how metformin induces molecular alterations in the endometrial tissues under PCOS conditions is not completely clear. Here, we recruited 7 non-PCOS patients during the proliferative phase (nPCOS), 7 non-PCOS patients with endometrial hyperplasia (nPCOSEH), 14 PCOS patients during the proliferative phase (PCOS), and 3 PCOS patients with endometrial hyperplasia (PCOSEH). Our studies demonstrated that compared with nPCOS, PCOS patients showed decreased Claudin 1 and increased Vimentin and Slug proteins. Similar to increased Slug protein, nPCOSEH and PCOSEH patients showed increased N-cadherin protein. Western blot and immunostaining revealed increased epithelial phosphorylated Cytokeratin 8 (p-CK 8) expression and an increased p-CK 8:CK 8 ratio in PCOS, nPCOSEH, and PCOSEH patients compared to nPCOS patients. Although nPCOSEH and PCOSEH patients showed increased p-ERK1/2 and/or p38 protein levels, the significant increase in p-ERK1/2 expression and p-ERK1/2:ERK1/2 ratio was only found in PCOS patients compared to nPCOS patients. A significant induction of the membrane ERβ immunostaining was observed in the epithelial cells of PCOS and PCOSEH patients compared to nPCOS and nPCOSEH patients. While in-vitro treatment with metformin alone increased Snail and decreased Claudin 1, N-cadherin and α-SMA proteins, concomitant treatment with metformin and E2 increased the expression of CK 8 and Snail proteins and decreased the expression of Claudin 1, ZO-1, Slug and α-SMA proteins. Our findings suggest that the EMT contributes to the switch from a healthy state to a PCOS state in the endometrium, which might subsequently drive endometrial injury and dysfunction. We also provide evidence that metformin differentially modulates EMT protein expression in PCOS patients depending on estrogenic stimulation.

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