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Hum Reprod. 2015 Jan;30(1):149-58. doi: 10.1093/humrep/deu288. Epub 2014 Nov 5.

Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis.

Author information

1
Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan.
2
Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan tani4327@med.tottori-u.ac.jp.
3
Division of Laboratory Animal Science, Research Center for Bioscience and Technology, Tottori University Faculty of Medicine, Yonago, Japan.
4
Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Japan.
5
Dermatology, Tottori University Faculty of Medicine, Yonago, Japan.

Abstract

STUDY QUESTION:

What is the role of the inhibitor of apoptosis proteins (IAPs) in human endometriotic tissues and a mouse model of endometriosis?

SUMMARY ANSWER:

Four IAP proteins were expressed in endometriotic tissue indicating IAPs may be a key factor in the pathogenesis and progression of endometriosis.

WHAT IS KNOWN ALREADY:

Overexpression of IAPs protects against a number of proapoptotic stimuli. IAPs (c-IAP1, c-IAP2, XIAP and Survivin) are expressed in human ectopic endometrial stromal cells (ESCs) from ovarian endometriomas.

STUDY DESIGN, SIZE, DURATION:

Forty-eight women with or without ovarian endometrioma are included in this study. BALB/c mice (n = 24) were used for the mouse endometriosis model. Mice with surgically induced endometriosis were treated with an IAP antagonist (BV6) for 4 weeks.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Human ectopic endometrial tissues from chocolate cysts and eutopic endometrial tissue were collected. ESCs were enzymatically isolated from these tissues. ESC proliferation was examined by 5-bromo-2'-deoxyuridine-enzyme-linked immunosorbent assay. IAPs expression in tissue derived from eutopic endometria and chocolate cysts was evaluated using real-time RT-PCR and immunohistochemistry. A homologous mouse endometriosis model was established by transplanting donor mouse uterine tissue into the abdominal cavities of recipient mice. After treating the mice with BV6 (i.p. 10 mg/ml), the extent of endometriosis-like lesions in mice was measured and proliferative activity assessed by Ki67 staining. All experiments were repeated a minimum of three times.

MAIN RESULTS AND THE ROLE OF CHANCE:

IAP (c-IAP1, c-IAP2, XIAP and Survivin) mRNA and protein in human ectopic endometrial tissues were expressed at higher levels than in eutopic endometrial tissues (P < 0.05). All four IAPs proteins were expressed in mouse endometriosis-like implants. BV6 inhibited BrdU incorporation of human ESCs (P < 0.05 versus control). BV6 also decreased the total number, weight, surface area and Ki67 positive cells in the endometriosis-like lesions in the mice (P < 0.05 versus control).

LIMITATIONS, REASONS FOR CAUTION:

Endometriotic lesions were surgically induced in mice by transplanting mouse uterine tissue only, not human pathological endometriotic tissue. Furthermore, the effects of BV6 on human ESCs and mouse endometriosis-like lesions may differ between the species.

WIDER IMPLICATIONS OF THE FINDINGS:

Our data support the hypothesis that IAPs are involved in the development of endometriosis, and therefore an inhibitor of IAPs has potential as a novel treatment for endometriosis.

STUDY FUNDING/COMPETING INTERESTS:

This work was supported by KAKENHI (Japan Society for the Promotion of Science, Grant-in-Aid: to F.T.; 21592098 and to T.H.; 24659731) and Yamaguchi Endocrine Research Foundation. The authors have no conflicts of interest to disclose.

KEYWORDS:

BV6; endometrial stromal cells; inhibitor of apoptosis proteins family; mouse endometriosis model

PMID:
25376458
PMCID:
PMC4262468
DOI:
10.1093/humrep/deu288
[Indexed for MEDLINE]
Free PMC Article

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