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miR-503, a microRNA epigenetically repressed in endometriosis, induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells.
Hum Reprod. 2016 11; 31(11):2587-2597.HR

Abstract

STUDY QUESTION

Is the micro-RNA (miRNA) miR-503, downregulated in endometriotic cyst stromal cells (ECSCs) and does this affect the cell cycle, cell proliferation, angiogenesis and contractility of these cells? SUMMARY ANSWER: miR-503 expression is downregulated in ECSCs by DNA hypermethylation and this contributes to their proliferation, resistance to apoptosis, extracellular matrix (ECM) contractility and angiogenesis through effects on cyclin D1, B-cell lymphoma/leukemia (Bcl)-2, Ras homology A and vascular endothelial growth factor A (VEGF-A).

WHAT IS KNOWN ALREADY

A variety of miRNAs are demonstrated to involve in the pathogenesis of endometriosis. miR-503 is a miRNA with tumor-suppressor functions, whose expression is suppressed in ECSCs.

STUDY DESIGN, SIZE, DURATION

We isolated ECSCs and normal endometrial stromal cells (NESCs) from ovarian endometriotic tissues (n = 32) and eutopic endometrial tissues without endometriosis (n = 8), respectively.

PARTICIPANTS/MATERIALS, SETTING, METHODS

We investigated the functions of miR-503 by using miR-503-transfected ECSCs and the DNA methylation status of miR-503 gene in ECSCs and NESCs by combined bisulfite restriction analysis.

MAIN RESULTS AND THE ROLE OF CHANCE

In ECSCs, miR-503 is downregulated by the DNA hypermethylation of its gene. The transfection of miR-503 into ECSCs resulted in the inhibition of cell proliferation and induction of cell-cycle arrest at G0/G1 phase through the suppression of cyclin D1, the induction of apoptosis through Bcl-2 suppression, the inhibition of VEGF-A production and the attenuation of ECM contractility via the suppression of Rho/Rho-associated coiled-coil-forming protein kinase-pathways.

LARGE SCALE DATA

NA.

LIMITATIONS, REASONS FOR CAUTION

The present experiments were carried out only with the stromal component of endometriosis and eutopic endometrium. The experiments with the eutopic endometrial stromal cells from women with endometriosis are not performed.

WIDER IMPLICATIONS OF THE FINDINGS

Our findings indicate that epigenetically repressed miR-503 in ECSCs is involved in the acquisition of endometriosis-specific cellular functions.

STUDY FUNDING/COMPETING INTERESTS

This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 13237327 to K.N., no. 26861335 to K.K. and no. 23592407 to H.N.) and the Kanzawa Medical Research Foundation (to K.K.). There are no conflicts of interest to declare.

Authors+Show Affiliations

Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan nasu@oita-u.ac.jp. Division of Obstetrics and Gynecology, Support System for Community Medicine, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan. Genetic Counselling Office, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27619772

Citation

Hirakawa, Tomoko, et al. "MiR-503, a microRNA Epigenetically Repressed in Endometriosis, Induces Apoptosis and Cell-cycle Arrest and Inhibits Cell Proliferation, Angiogenesis, and Contractility of Human Ovarian Endometriotic Stromal Cells." Human Reproduction (Oxford, England), vol. 31, no. 11, 2016, pp. 2587-2597.
Hirakawa T, Nasu K, Abe W, et al. MiR-503, a microRNA epigenetically repressed in endometriosis, induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells. Hum Reprod. 2016;31(11):2587-2597.
Hirakawa, T., Nasu, K., Abe, W., Aoyagi, Y., Okamoto, M., Kai, K., Takebayashi, K., & Narahara, H. (2016). MiR-503, a microRNA epigenetically repressed in endometriosis, induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells. Human Reproduction (Oxford, England), 31(11), 2587-2597.
Hirakawa T, et al. MiR-503, a microRNA Epigenetically Repressed in Endometriosis, Induces Apoptosis and Cell-cycle Arrest and Inhibits Cell Proliferation, Angiogenesis, and Contractility of Human Ovarian Endometriotic Stromal Cells. Hum Reprod. 2016;31(11):2587-2597. PubMed PMID: 27619772.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - miR-503, a microRNA epigenetically repressed in endometriosis, induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells. AU - Hirakawa,Tomoko, AU - Nasu,Kaei, AU - Abe,Wakana, AU - Aoyagi,Yoko, AU - Okamoto,Mamiko, AU - Kai,Kentaro, AU - Takebayashi,Kanetoshi, AU - Narahara,Hisashi, Y1 - 2016/09/12/ PY - 2016/03/09/received PY - 2016/06/20/revised PY - 2016/08/05/accepted PY - 2016/9/14/pubmed PY - 2018/1/13/medline PY - 2016/9/14/entrez KW - DNA methylation KW - angiogenesis KW - apoptosis KW - cell cycle KW - cell proliferation KW - contractility KW - cyclin D1 KW - endometriosis KW - micro-RNA SP - 2587 EP - 2597 JF - Human reproduction (Oxford, England) JO - Hum. Reprod. VL - 31 IS - 11 N2 - STUDY QUESTION: Is the micro-RNA (miRNA) miR-503, downregulated in endometriotic cyst stromal cells (ECSCs) and does this affect the cell cycle, cell proliferation, angiogenesis and contractility of these cells? SUMMARY ANSWER: miR-503 expression is downregulated in ECSCs by DNA hypermethylation and this contributes to their proliferation, resistance to apoptosis, extracellular matrix (ECM) contractility and angiogenesis through effects on cyclin D1, B-cell lymphoma/leukemia (Bcl)-2, Ras homology A and vascular endothelial growth factor A (VEGF-A). WHAT IS KNOWN ALREADY: A variety of miRNAs are demonstrated to involve in the pathogenesis of endometriosis. miR-503 is a miRNA with tumor-suppressor functions, whose expression is suppressed in ECSCs. STUDY DESIGN, SIZE, DURATION: We isolated ECSCs and normal endometrial stromal cells (NESCs) from ovarian endometriotic tissues (n = 32) and eutopic endometrial tissues without endometriosis (n = 8), respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: We investigated the functions of miR-503 by using miR-503-transfected ECSCs and the DNA methylation status of miR-503 gene in ECSCs and NESCs by combined bisulfite restriction analysis. MAIN RESULTS AND THE ROLE OF CHANCE: In ECSCs, miR-503 is downregulated by the DNA hypermethylation of its gene. The transfection of miR-503 into ECSCs resulted in the inhibition of cell proliferation and induction of cell-cycle arrest at G0/G1 phase through the suppression of cyclin D1, the induction of apoptosis through Bcl-2 suppression, the inhibition of VEGF-A production and the attenuation of ECM contractility via the suppression of Rho/Rho-associated coiled-coil-forming protein kinase-pathways. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: The present experiments were carried out only with the stromal component of endometriosis and eutopic endometrium. The experiments with the eutopic endometrial stromal cells from women with endometriosis are not performed. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that epigenetically repressed miR-503 in ECSCs is involved in the acquisition of endometriosis-specific cellular functions. STUDY FUNDING/COMPETING INTERESTS: This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 13237327 to K.N., no. 26861335 to K.K. and no. 23592407 to H.N.) and the Kanzawa Medical Research Foundation (to K.K.). There are no conflicts of interest to declare. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/27619772/miR_503_a_microRNA_epigenetically_repressed_in_endometriosis_induces_apoptosis_and_cell_cycle_arrest_and_inhibits_cell_proliferation_angiogenesis_and_contractility_of_human_ovarian_endometriotic_stromal_cells_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/dew217 DB - PRIME DP - Unbound Medicine ER -