Role of Epithelial-Mesenchymal Transition in Human Adenomyosis: A New Insight into Its Pathogenesis
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.
KeywordsAdenomyosis Basalis endometrium HGF EMT Pathogenesis
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.
- 5.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.Google Scholar
- 8.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.Google Scholar
- 13.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.Google Scholar
- 14.Setoguchi T. Histology of endometrium (in Japanese). In: Suzuku S, editor. Textbook of practical histology. Tokyo: Nanzando Co. Ltd.; 1979. p. 218–41.Google Scholar
- 24.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.Google Scholar