Role of Epithelial-Mesenchymal Transition in Human Adenomyosis: A New Insight into Its Pathogenesis

In: Comprehensive Gynecology and Obstetrics · 2018 · pp. 129–140 · doi:10.1007/978-981-10-7167-6_9 · W2807875533
book-chapter OA: closed CC0
Full text JSON View on OpenAlex View at publisher
AI-generated summary by gemini-2.5-flash-lite+body, 2026-06-13

Hepatocyte growth factor and estrogen induce epithelial-mesenchymal transition by regulating SLUG/SNAIL expression in human adenomyosis.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

AI-generated deep summary by claude@2026-06, 2026-06-07 · read from full text

This chapter investigates whether hepatocyte growth factor (HGF) and estrogen promote epithelial-mesenchymal transition (EMT) as a mechanism underlying gland invagination in human adenomyosis. Biopsy specimens spanning endometrium to myometrium were collected after hysterectomy from women with and without adenomyosis, and the relationship between HGF and E-cadherin/N-cadherin was assessed by qRT-PCR and immunohistochemistry; mechanistic experiments used Ishikawa cells to examine SLUG and SNAIL expression under HGF and estrogen, including inhibition with anti-HGF antibody or an estrogen receptor antagonist. The authors report that HGF downregulated E-cadherin and upregulated N-cadherin in endometrial epithelial cells, with an inverse HGF–E-cadherin relationship in basalis endometrium from women with adenomyosis, and that HGF plus estrogen increased SLUG/SNAIL expression additively, which was abrogated by pathway inhibition; they also observed HGF-induced morphological changes and migration. The paper acknowledges adenomyosis pathogenesis remains elusive and frames its findings as mechanistic support for the accepted gland invagination concept. This paper is centrally about endometriosis and/or adenomyosis — specifically, it focuses on EMT driven by HGF and estrogen in human adenomyosis.

Read from the paper's body, not the abstract. Not a substitute for reading the paper. No clinical advice. How this works

Full text 8,989 characters · extracted from oa-doi-fallback · 2 sections · click to expand

Abstract

The exact pathogenesis of adenomyosis is still elusive. Among different reported concepts, direct invagination of gland cells from basalis endometrium deep into myometrium is the most widely accepted opinion in the development of adenomyosis. To address the mechanistic basis of this accepted concept, we investigated the role of hepatocyte growth factor (HGF) and estrogen in the occurrence of epithelial-mesenchymal transition (EMT) in human adenomyosis. 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)/N-cadherin (mesenchymal cell marker) was examined using endometrial epithelial cells (EECs) and tissues by qRT-PCR and immunohistochemistry. The gene and protein expressions of two transcriptional repressors of E-cadherin, SLUG and SNAIL, were examined using Ishikawa cells. HGF downregulated E-cadherin and upregulated N-cadherin mRNA expression in EECs, and an inverse relationship between HGF and E-cadherin was observed in basalis endometria of women with adenomyosis. HGF induced morphological changes and promoted migration of EECs. Ishikawa cells exhibited upregulation of SLUG/SNAIL gene expression in response to HGF and estrogen with an additive effect between them. HGF- and estrogen-promoted SLUG/SNAIL gene expression was significantly abrogated after pretreatment of cells with anti-HGF antibody or ICI 182720, an estrogen receptor antagonist. Our findings suggested that HGF either alone or in combination with estrogen may be involved in gland invagination deep into myometrium by inducing EMT in women with adenomyosis. Access this chapter Tax calculation will be finalised at checkout Purchases are for personal use only Similar content being viewed by others

References

Bergeron C, Amant F, Ferenczy A. Pathology and pathophysiology of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):511–21. Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update. 1998;4(4):312–22. Wang PH, Fuh JL, Chao HT, Liu WM, Cheng MH, Chao KC. Is the surgical approach beneficial to subfertile women with symptomatic extensive adenomyosis? J Obstet Gynecol Res. 2009;35:495–502. Ridley JH. The histogenesis of endometriosis: a review of facts and fancies. Obstet Gynecol Surv. 1968;23:1–35. Hay ED. Organization and fine structure of epithelium and mesenchyme in the development of chick embryo. In: Fleischmajer R, Billingham RE, editors. Epithelial-mesenchymal interactions. Baltimore: Williams & Wilkins; 1968. p. 31–55. Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grubel G, Legrand JF, Als-Nielsen J, Colman DR, Hendrickson WA. Structural basis of cell-cell adhesion by cadherins. Nature. 1995;374:327–37. Gaetje R, Kotzian S, Herrmann G, Baumann R, Starzinski-Powitz A. Nonmalignant epithelial cells, potentially invasive in human endometriosis, lacks the tumor suppressor molecule E-cadherin. Am J Pathol. 1997;150:461–7. Hiscox S, Jiang WG. HGF/SF regulates the phosphorylation of β-catenin and cell-cell adhesion in cancer cells. Proc Am Assoc Cancer Res. 1998;39:500–1. Chen YJ, Li HY, Huang CH, Twu NF, Yen MS, Wang PH, Chou TY, Liu YN, Chao KC, Yang MH. Estrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis. J Pathol. 2010;222:261–70. Park SH, Cheung LWT, Wong AST, Leung PCK. Estrogen regulates Snail and Slug in the down-regulation of E-cadherin and induces mestastatic potential of ovarian cancer cells through estrogen receptorα. Mol Endocrinol. 2008;22:2085–98. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA. The transcriptional factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116:499–511. Hendrickson MR, et al. Normal histology of the uterus and fallopian tubes. In: Sternberg SS, editor. Histology for pathologists. 2nd ed. Philadelphia: Lippincott-Raven; 1997. p. 894–7. Setoguchi T. Histology of endometrium (in Japanese). In: Suzuku S, editor. Textbook of practical histology. Tokyo: Nanzando Co. Ltd.; 1979. p. 218–41. Khan KN, Fujishita A, Kitajima M, Masuzaki H, Nakashima M, Kitawaki J. Biological differences between functionalis and basalis endometria in women with and without adenomyosis. Eur J Obstet Gynecol Reprod Biol. 2016;203:49–55. Khan KN, Kitajima M, Imamura T, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H. Toll-like receptor 4 (TLR4)-mediated growth of endometriosis by human heat shock protein 70 (Hsp70). Hum Reprod. 2008;23(10):2210–9. Imamura T, Khan KN, Fujishita A, Kitajima M, Hiraki K, Ishimaru T, Masuzaki H. Effect of GnRH agonist therapy on the expression of human heat shock protein 70 in eutopic and ectopic endometria of women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2014;180:16–23. Khan KN, Kitajima M, Hiraki K, Fujishita A, Nakashima M, Masuzaki H. Involvement of hepatocyte growth factor-induced epithelial-mesenchymal transition in human adenomyosis. Biol Reprod. 2015;92(2):35. Khan KN, Masuzaki H, Fujishita A, Kitajima M, Sekine I, Ishimaru T. Immunoexpression of hepatocyte growth factor and c-Met receptor in the eutopic endometrium predicts the activity of ectopic endometrium. Fertil Steril. 2003;79(1):173–81. Khan KN, Kitajima M, Hiraki H, Fujishita A, Sekine I, Ishimaru T, Masuzaki H. Immunopathogenesis of pelvic endometriosis: role of hepatocyte growth factor, macrophages and ovarian steroids. Am J Reprod Immunol. 2008;60:383–404. Khan KN, Masuzaki H, Fujishita A, Kitajima M, Kohno T, Sekine I, Matsuyama T, Ishimaru T. Regulation of hepatocyte growth factor by basal and stimulated-macrophages in women with endometriosis. Hum Reprod. 2005;20:49–60. Khan KN, Masuzaki H, Fujishita A, Kitajima M, Sekine I, Matsuyama T, Ishimaru T. Estrogen and progesterone receptor expression in macrophages and regulation of hepatocyte growth factor by ovarian steroids in women with endometriosis. Hum Reprod. 2005;20:2004–13. Fujishita A, Nakane PK, Koji T, Masuzaki H, Chavez RO, Yamabe T, Ishimaru T. Expression of estrogen and progesterone in endometrium and peritoneal endometriosis: an immunohistochemical and in situ hybridization study. Fertil Steril. 1997;67:856–64. Khan KN, Kitajima M, Fujishita A, Ishimaru T, Sekine I, Masuzaki H. Multifunctional role of hepatocyte growth factor in the development of pelvic endometriosis. WES E-J. 2008;13–20. Hannan NJ, Paiva P, Dimitriadis E, Salamonsen LA. Models for study of human embryo implantation: choice of cell lines? Biol Reprod. 2010;82:235–45. Castelbaum AJ, Ying L, Samkuti SG, Sun J, IIesanmi AO, Lessey BA. Characterization of integrin expression in a well differentiated endometrial adenocarcinoma cell line (Ishikawa). J Clin Endocrinol Metab. 1997;82:136–42. Montserrat N, Mozos A, Llobet D, Dolcet X, Pons C, Garcia de Herreros A, Matias-Guiu X, Prat J. Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma. Hum Pathol. 2012;43:632–43. Zeitvogel A, Baumann R, Starzinski-Powitz A. Identification of an invasive, N-cadherin-expressing epithelial cell type in endometriosis using a new cell culture model. Am J Pathol. 2001;159:1839–52. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 2009;119:1438–49. Acknowledgment This work was supported in part by Grants-in-Aid for Scientific Research (grants 21592101 and 24592474) from the Japan Society of the Promotion of Science (to K.N.K.). I gratefully thank Dr. Akira Fujishita and Dr. Koichi Hiraki of Saikeikai Nagasaki Hospital and Dr. Michio Kitajima of Nagasaki University Hospital for their kind assistance in sample collection and Prof. Masahiro Nakashima for his experimental advice. K.N.K. designed and supervised the project and edited/wrote the complete draft. Author information Authors and Affiliations Corresponding author Editor information Editors and Affiliations Rights and permissions Copyright information © 2018 Springer Nature Singapore Pte Ltd. About this chapter Cite this chapter Khan, K.N. (2018). Role of Epithelial-Mesenchymal Transition in Human Adenomyosis: A New Insight into Its Pathogenesis. In: Sugino, N. (eds) Uterine Fibroids and Adenomyosis. Comprehensive Gynecology and Obstetrics. Springer, Singapore. https://doi.org/10.1007/978-981-10-7167-6_9 Download citation DOI: https://doi.org/10.1007/978-981-10-7167-6_9 Published: Publisher Name: Springer, Singapore Print ISBN: 978-981-10-7166-9 Online ISBN: 978-981-10-7167-6 eBook Packages: MedicineMedicine (R0)

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

Ask this paper AI returns verbatim quotes from the full text · source: oa-doi-fallback

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Condition tags

adenomyosis

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (28)

Source provenance

openalex
last seen: 2026-06-10T17:14:06.276822+00:00
unpaywall
last seen: 2026-09-12T07:21:10.926195+00:00
License: CC0 · commercial use OK