Notch-1 Signaling Activation and Progesterone Receptor Expression in Ectopic Lesions of Women With Endometriosis.
Notch-1 Signaling Activation and Progesterone Receptor Expression in Ectopic Lesions of Women With Endometriosis.
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DOI：
10.1210/js.2018-00007
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发表时间：
2018-07-01
影响因子：
4.1
通讯作者：
Simmen RCM
中科院分区：
文献类型：
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作者：
Brown DM;Lee HC;Liu S;Quick CM;Fernandes LM;Simmen FA;Tsai SJ;Simmen RCM
黄体酮 (P) 抵抗是子宫内膜异位症的一个标志，但 P 敏感性丧失导致病变形成的潜在机制仍知之甚少。评估子宫内膜异位症进展中 Notch-1 信号激活与 P 抵抗之间的关联。病例对照研究；存档的福尔马林固定、石蜡包埋的组织。大学医院（美国、台湾）。患有子宫内膜异位症的女性；人子宫内膜基质细胞系（HESC）。在位子宫内膜（EU）和异位病变（EC）是从手术诊断的患者中收集的。确定了 EU 和 EC 的存档组织切片。用 N-[N-(3,5-二氟苯乙酰基)-l-丙氨酰]-S-苯基甘氨酸叔丁酯 (DAPT) 和丙戊酸 (VPA) 处理 HESC，分别抑制和诱导 Notch-1 激活。通过免疫组织化学分析组织的 Notch 细胞内结构域 1 (NICD1) 和孕酮受体 (PGR) 蛋白表达，并通过定量逆转录聚合酶链反应分析 NICD1 靶基因 HES1、PGR 和 PGR-B 的转录水平。评估经过 DAPT 或 VPA 处理的 HESC（有或没有 P 共处理）的细胞数量以及 PGR、HES1 和 PGR 靶基因 DKK1 转录水平。在欧盟和欧共体中，核定位的基质 NICD1 蛋白水平与总 PGR 呈负相关。基质 EC 表现出比 EU 更高的 HES1 和更低的总 PGR 和 PGR-B 转录水平。在 HESC 中，NICD1 的 DAPT 减少减少了细胞数量，增加了 PGR 转录物和核 PGR 蛋白水平，并且在 P 共处理下，维持了 P 敏感性。相反，VPA 诱导的 NICD1 降低了 PGR 转录物水平，并且在 P 共同处理下，消除了 P 诱导的 DKK1 并维持了 HES1 转录物水平。异常的 Notch-1 激活与 PGR 降低有关，从而导致子宫内膜异位症中的 P 抗性。 Notch-1 激活与子宫内膜异位症患者异位病变中孕酮受体表达的丧失以及子宫内膜基质细胞中孕酮敏感性的丧失相关。
Progesterone (P) resistance is a hallmark of endometriosis, but the underlying mechanism(s) for loss of P sensitivity leading to lesion establishment remains poorly understood. To evaluate the association between Notch-1 signaling activation and P resistance in the progression of endometriosis. Case control study; archived formalin-fixed, paraffin-embedded tissues. University hospitals (United States, Taiwan). Women with endometriosis; human endometrial stromal cell line (HESC). Eutopic endometria (EU) and ectopic lesions (ECs) were collected from surgically diagnosed patients. Archived tissue sections of EU and ECs were identified. HESCs were treated with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) and valproic acid (VPA) to, respectively, suppress and induce Notch-1 activation. Tissues were analyzed for Notch Intra-Cellular Domain 1 (NICD1) and progesterone receptor (PGR) protein expression by immunohistochemistry and for transcript levels of NICD1 target genes HES1, PGR, and PGR-B by quantitative reverse transcription polymerase chain reaction. DAPT- or VPA-treated HESCs with and without P cotreatment were evaluated for cell numbers and for PGR, HES1, and PGR target gene DKK1 transcript levels. Nuclear-localized stromal NICD1 protein levels were inversely associated with those of total PGR in EU and ECs. Stromal ECs displayed higher HES1 and lower total PGR and PGR-B transcript levels than EU. In HESCs, DAPT reduction of NICD1 decreased cell numbers and increased PGR transcript and nuclear PGR protein levels and, with P cotreatment, maintained P sensitivity. Conversely, VPA induction of NICD1 decreased PGR transcript levels and, with P cotreatment, abrogated P-induced DKK1 and maintained HES1 transcript levels. Aberrant Notch-1 activation is associated with decreased PGR that contributes to P resistance in endometriosis. Notch-1 activation is associated with loss of progesterone receptor expression in ectopic lesions of endometriotic patients and with loss of progesterone sensitivity in endometrial stromal cells.