CCN2 Mediates S1P-Induced Upregulation of COX2 Expression in Human Granulosa-Lutein Cells
CCN2 Mediates S1P-Induced Upregulation of COX2 Expression in Human Granulosa-Lutein Cells
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CCN2 介导 S1P 诱导的人颗粒叶黄素细胞中 COX2 表达的上调
DOI：
10.3390/cells8111445
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发表时间：
2019-11
期刊：
影响因子：
6
通讯作者：
Leung Peter C. K.
中科院分区：
文献类型：
--
作者：
Hu Liao-Liao;Chang Hsun-Ming;Yi Yuyin;Liu Yingtao;Taylor Elizabeth L.;Zheng Li-Ping;Leung Peter C. K.
CCN 1和CCN 2是CCN家族的成员，在多种女性生殖功能（包括排卵）的调节中发挥重要作用。环氧合酶-2（COX 2）是排卵的关键介质，可由1-磷酸鞘氨醇（S1 P）通过S1 P 1/3介导的Yes相关蛋白（雅普）信号传导诱导。然而，目前尚不清楚CCN 1或CCN 2是否可以介导S1 P诱导的COX 2表达上调和人颗粒体-叶黄素（hGL）细胞中前列腺素E2（PGE 2）产生的增加。在本研究中，我们研究了S1 P对hGL细胞中CCN 1和CCN 2表达的影响。此外，我们使用了双重抑制方法（siRNA介导的沉默和小分子抑制剂）来研究S1 P效应的分子机制。我们的研究结果表明，S1 P处理显着上调CCN 1和CCN 2的表达在hGL细胞中的浓度依赖性的方式。此外，抑制或沉默S1 P1，而不是S1 P3，完全消除了S1 P诱导的CCN 2表达上调。此外，我们证明了S1 P诱导的雅普核转位和雅普的抑制或沉默完全消除了S1 P诱导的CCN 1和CCN 2表达上调。值得注意的是，沉默CCN 2，而不是CCN 1，完全逆转了S1 P诱导的COX 2表达上调和PGE 2产生增加。因此，在hGL细胞中，CCN 2通过S1 P1介导的信号通路介导S1 P诱导的COX 2表达上调。我们的研究结果扩展了我们对人类卵巢中S1 P介导的细胞活动的分子机制的理解。
CCN1 and CCN2 are members of the CCN family and play essential roles in the regulation of multiple female reproductive functions, including ovulation. Cyclooxygenase-2 (COX2) is a critical mediator of ovulation and can be induced by sphingosine-1-phosphate (S1P) through the S1P1/3-mediated Yes-associated protein (YAP) signaling. However, it is unclear whether CCN1 or CCN2 can mediate S1P-induced upregulation of COX2 expression and increase in prostaglandin E2 (PGE2) production in human granulosa-lutein (hGL) cells. In the present study, we investigated the effects of S1P on the expressions of CCN1 and CCN2 in hGL cells. Additionally, we used a dual inhibition approach (siRNA-mediated silencing and small molecular inhibitors) to investigate the molecular mechanisms of S1P effects. Our results showed that S1P treatment significantly upregulated the expression of CCN1 and CCN2 in a concentration-dependent manner in hGL cells. Additionally, inhibition or silencing of S1P1, but not S1P3, completely abolished the S1P-induced upregulation of CCN2 expression. Furthermore, we demonstrated that S1P-induced nuclear translocation of YAP and inhibition or silencing of YAP completely abolished the S1P-induced upregulation of CCN1 and CCN2 expression. Notably, silencing of CCN2, but not CCN1, completely reversed the S1P-induced upregulation of COX2 expression and the increase in PGE2 production. Thus, CCN2 mediates the S1P-induced upregulation of COX2 expression through the S1P1-mediated signaling pathway in hGL cells. Our findings expand our understanding of the molecular mechanism underlying the S1P-mediated cellular activities in the human ovary.
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作者：
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