Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis
Inhibitor of apoptosis proteins (IAPs) may be effective therapeutic targets for treating endometriosis
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凋亡蛋白抑制剂（IAP）可能是治疗子宫内膜异位症的有效治疗靶点
DOI：
10.1093/humrep/deu288
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发表时间：
2015
期刊：
影响因子：
6.1
通讯作者：
Harada T
中科院分区：
文献类型：
--
作者：
Ueagaki T;Taniguchi F;Nakamura K;Osaki M;Okada F;Yamamoto O;Harada T
研究问题凋亡抑制蛋白（IAP）在人类子宫内膜异位症组织和小鼠子宫内膜异位症模型中的作用是什么？综述答案子宫内膜异位症组织中有四种IAP蛋白表达，表明IAP可能是子宫内膜异位症发病机制和进展的关键因素。IAP（c-IAP 1、c-IAP 2、XIAP和Survivin）在来自卵巢腺瘤的人异位子宫内膜间质细胞（ESCs）中表达。研究设计、大小、持续时间48名患有或不患有卵巢腺瘤的妇女包括在本研究中。BALB/c小鼠（n= 24）用于小鼠子宫内膜异位症模型。用IAP拮抗剂（BV 6）治疗手术诱导的子宫内膜异位症小鼠4 wk。对象/材料、地点、方法收集巧克力囊肿异位内膜组织和在位内膜组织。从这些组织中酶促分离ESC。5-溴-2 ′-脱氧尿苷酶联免疫吸附试验检测ESC增殖情况。采用实时荧光定量RT-PCR和免疫组织化学方法检测了原位膀胱和巧克力囊肿组织中IAP的表达。将供体小鼠子宫组织移植到受体小鼠腹腔内，建立小鼠子宫内膜异位症模型。在用BV 6（i.p.10mg/ml）处理小鼠后，测量小鼠中类增生病变的程度，并通过Ki 67染色评估增殖活性。主要结果和CHANCEIAP（c-IAP 1、c-IAP 2、XIAP和Survivin）mRNA和蛋白在人异位子宫内膜组织中的表达水平高于在位子宫内膜组织（P< 0.05）。所有四种IAP蛋白在小鼠类牙周炎植入物中表达。BV 6抑制人ESCs的BrdU掺入（P< 0.05）。BV 6还降低了小鼠子宫内膜异位样病变中的总数量、重量、表面积和Ki 67阳性细胞（与对照相比P< 0.05）。此外，BV 6对人ESC和小鼠子宫内膜异位样病变的作用可能在物种之间不同。发现的更广泛的含义我们的数据支持IAP参与子宫内膜异位症的发展的假设，因此IAP的抑制剂有可能作为子宫内膜异位症的新治疗方法。补助金：给予F.T.; 21592098和T.H.; 24659731）和山口内分泌研究基金会。作者没有利益冲突需要披露。
STUDY QUESTIONWhat is the role of the inhibitor of apoptosis proteins (IAPs) in human endometriotic tissues and a mouse model of endometriosis?SUMMARY ANSWERFour IAP proteins were expressed in endometriotic tissue indicating IAPs may be a key factor in the pathogenesis and progression of endometriosis.WHAT IS KNOWN ALREADYOverexpression 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, DURATIONForty-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, METHODSHuman 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 CHANCEIAP (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 CAUTIONEndometriotic 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 FINDINGSOur 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 INTEREST(S)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.