Impact of growth hormone-releasing hormone antagonist on decidual stromal cell growth and apoptosis in vitro†.
Impact of growth hormone-releasing hormone antagonist on decidual stromal cell growth and apoptosis in vitro†.
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生长激素释放激素拮抗剂对体外蜕膜基质细胞生长和凋亡的影响。
DOI：
10.1093/biolre/ioab214
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发表时间：
2022
影响因子：
3.6
通讯作者：
Wang,Hsin-Shih
中科院分区：
文献类型：
--
作者：
Wu,Hsien-Ming;Chen,Liang-Hsuan;Schally,AndrewV;Huang,Hong-Yuan;Soong,Yung-Kuei;Leung,PeterCK;Wang,Hsin-Shih
子宫内膜间质细胞重塑在人类妊娠过程中至关重要。生长激素释放激素及其功能性受体在妇科肿瘤细胞和在位子宫内膜间质细胞中均有表达。近年来的研究表明，生长激素释放激素拮抗剂可直接拮抗妇科肿瘤局部产生的生长激素释放激素，具有潜在的临床应用价值。然而，生长激素释放激素拮抗剂对正常子宫内膜间质细胞生长的影响仍有待阐明。本研究旨在探讨生长激素释放激素拮抗剂（JMR-132）对人蜕膜基质细胞增殖和凋亡的影响及其分子机制。我们的研究结果表明，生长激素释放激素和生长激素释放激素受体的剪接变异体1表达的人蜕膜基质细胞分离自早孕妇女接受手术流产的蜕膜组织。此外，用JMR-132处理基质细胞诱导细胞凋亡，增加裂解的caspase-3和caspase-9活性，并以时间和剂量依赖性方式降低细胞活力。使用双重抑制方法（药理学抑制剂和siRNA介导的敲低），我们发现JMR-132诱导的凋亡信号激活是由ERK 1/2和JNK信号通路的激活以及随后的GADD 45 α上调介导的。总之，JMR-132通过激活ERK 1/2和JNK介导的人子宫内膜间质细胞中GADD 45 α上调诱导细胞凋亡来抑制蜕膜间质细胞的细胞存活。我们的研究结果为生长激素释放激素拮抗剂对人类蜕膜编程的潜在影响提供了新的见解。
Endometrial stromal cells remodeling is critical during human pregnancy. Growth hormone-releasing hormone and its functional receptor have been shown to be expressed in gynecological cancer cells and eutopic endometrial stromal cells. Recent studies have demonstrated the potential clinical uses of antagonists of growth hormone-releasing hormone as effective antitumor agents because of its directly antagonistic effect on the locally produced growth hormone-releasing hormone in gynecological tumors. However, the impact of growth hormone-releasing hormone antagonists on normal endometrial stromal cell growth remained to be elucidated. The aim of this study was to investigate the effect of a growth hormone-releasing hormone antagonist (JMR-132) on cell proliferation and apoptosis of human decidual stromal cells and the underlying molecular mechanisms. Our results showed that growth hormone-releasing hormone and the splice variant 1 of growth hormone-releasing hormone receptor are expressed in human decidual stromal cells isolated from the decidual tissues of early pregnant women receiving surgical abortion. In addition, treatment of stroma cells with JMR-132 induced cell apoptosis with increasing cleaved caspase-3 and caspase-9 activities and decrease cell viability in a time- and dose-dependent manner. Using a dual inhibition approach (pharmacological inhibitors and siRNA-mediated knockdown), we showed that JMR-132-induced activation of apoptotic signals are mediated by the activation of ERK1/2 and JNK signaling pathways and the subsequent upregulation of GADD45alpha. Taken together, JMR-132 suppresses cell survival of decidual stromal cells by inducing apoptosis through the activation of ERK1/2- and JNK-mediated upregulation of GADD45alpha in human endometrial stromal cells. Our findings provide new insights into the potential impact of growth hormone-releasing hormone antagonist on the decidual programming in humans.