Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis.
OBJECTIVE
What is the role of the inhibitor of apoptosis proteins (IAPs) in human endometriotic tissues and a mouse model of endometriosis?


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


BACKGROUND
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.


METHODS
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.


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.


RESULTS
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).


CONCLUSIONS
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.


CONCLUSIONS
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.


BACKGROUND
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.
Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan.
Takashi
T
Uegaki
Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan tani4327@med.tottori-u.ac.jp.
Fuminori
F
Taniguchi
Division of Laboratory Animal Science, Research Center for Bioscience and Technology, Tottori University Faculty of Medicine, Yonago, Japan.
Kazuomi
K
Nakamura
Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Japan.
Mitsuhiko
M
Osaki
Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Japan.
Futoshi
F
Okada
Dermatology, Tottori University Faculty of Medicine, Yonago, Japan.
Osamu
O
Yamamoto
Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago 683-8504, Japan.
Tasuku
T
Harada
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C
D051034:Inhibitor of Apoptosis Proteins
BV6; endometrial stromal cells; inhibitor of apoptosis proteins family; mouse endometriosis model