Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis
Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis
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DOI：
10.1002/path.2761
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发表时间：
2010-11-01
影响因子：
7.3
通讯作者：
Yang, Muh-Hwa
中科院分区：
文献类型：
--
作者：
Chen, Yi-Jen;Li, Hsin-Yang;Yang, Muh-Hwa
子宫腺肌病是一种雌激素依赖性疾病，由子宫内膜向下延伸到子宫肌层引起。上皮间质转化（EMT）赋予细胞迁移和侵袭特性，并可由雌激素诱导。我们推测雌激素诱导的EMT在子宫腺肌病的发病机制中起关键作用。我们首先研究了子宫腺肌病病变是否发生EMT，以及EMT是否与血清17 β-雌二醇（E2）水平相关。对子宫腺肌病患者的子宫腺肌病病变和相应的在位子宫内膜样本进行免疫组化。无子宫内膜疾病的妇女的子宫内膜作为对照。在子宫腺肌病病变的上皮成分中，与在位子宫内膜相比，波形蛋白表达上调，E-cadherin表达下调，表明子宫腺肌病发生EMT。在子宫腺肌病中，血清E2水平与E-cadherin在在位子宫内膜和子宫腺肌病病变上皮成分中的表达呈负相关，表明雌激素诱导的EMT参与子宫内膜细胞。在雌激素受体阳性的石川子宫内膜上皮细胞中，雌激素诱导成纤维细胞样表型的形态学改变，从上皮标记表达转变为间质标记表达，增加迁移和侵袭，以及EMT调节因子Slug的上调。雷洛昔芬，一种选择性雌激素受体调节剂，消除了这些影响。为了确定雌激素诱导的EMT在异位子宫内膜植入中的作用，我们将子宫腺肌病患者的在位子宫内膜或子宫腺肌病病变异种移植到切除卵巢的SCID小鼠中。子宫内膜的着床是雌激素依赖性的，并被雷洛昔芬抑制。总的来说，这些数据突出了雌激素诱导的EMT在子宫腺肌病发展中的关键作用，并表明雷洛昔芬可能是子宫腺肌病患者的潜在治疗药物。(C)版权所有2010大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Adenomyosis is an oestrogen-dependent disease caused by a downward extension of the endometrium into the uterine myometrium. Epithelial-mesenchymal transition (EMT) endows cells with migratory and invasive properties and can be induced by oestrogen. We hypothesized that oestrogen-induced EMT is critical in the pathogenesis of adenomyosis. We first investigated whether EMT occurred in adenomyotic lesions and whether it correlated with serum 17 beta-oestradiol (E2) levels. Immunohistochemistry was performed on adenomyotic lesions and corresponding eutopic endometrium samples from women with adenomyosis. Endometria from women without endometrial disorders were used as a control. In the epithelial component of adenomyotic lesions, vimentin expression was up-regulated and E-cadherin expression was down-regulated compared to the eutopic endometrium, suggesting that EMT occurs in adenomyosis. In adenomyosis, the serum E2 level was negatively correlated with E-cadherin expression in the epithelial components of the eutopic endometrium and adenomyotic lesions, suggesting the involvement of oestrogen-induced EMT in endometrial cells. In oestrogen receptor-positive Ishikawa endometrial epithelial cells, oestrogen induced a morphological change to a fibroblast-like phenotype, a shift from epithelial marker expression to mesenchymal marker expression, increased migration and invasion, and up-regulation of the EMT regulator Slug. Raloxifene, a selective oestrogen receptor modulator, abrogated these effects. To determine the role of oestrogen-induced EMT in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium or adenomyotic lesions from adenomyosis patients into ovariectomized SCID mice. The implantation of endometrium was oestrogen-dependent and was suppressed by raloxifene. Collectively, these data highlight the crucial role of oestrogen-induced EMT in the development of adenomyosis and suggest that raloxifene may be a potential therapeutic agent for adenomyosis patients. (C) Copyright 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.