cAMP-Response Element-Binding 3-Like Protein 1 (CREB3L1) is Required for Decidualization and its Expression is Decreased in Women with Endometriosis.
cAMP-Response Element-Binding 3-Like Protein 1 (CREB3L1) is Required for Decidualization and its Expression is Decreased in Women with Endometriosis.
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DOI：
10.2174/1566524016666160225153659
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发表时间：
2016
影响因子：
2.5
通讯作者：
Jeong JW
中科院分区：
文献类型：
--
作者：
Ahn JI;Yoo JY;Kim TH;Kim YI;Ferguson SD;Fazleabas AT;Young SL;Lessey BA;Ahn JY;Lim JM;Jeong JW
子宫内膜异位症是不孕不育和盆腔疼痛的主要原因，影响10%以上的育龄妇女。孕酮反应基因和蛋白表达的改变证明了黄体酮抵抗在患有这种疾病的妇女子宫内膜中的存在。CAMP反应元件结合类3蛋白1(Creb3L1)已被高密度DNA芯片分析确定为小鼠子宫孕激素受体(PR)靶基因。然而，CREB3L1的功能尚未在子宫内膜异位症和子宫生物学的背景下进行研究。在这项研究中，我们验证了孕酮(P4)对野生型和孕酮受体基因敲除(PRKO)小鼠子宫中Creb3l1的调节。此外，我们还观察到CREB3L1在分泌期子宫内膜的表达显著高于增生期，而在子宫内膜异位症患者的子宫内膜中CREB3L1的表达显著降低。最后，在激素诱导体外蜕膜形成之前，通过将CREB3L1 siRNA导入培养的人子宫内膜基质细胞(HESCs)，我们发现CREB3L1是蜕膜形成过程所必需的。有趣的是，在CREB3L1沉默的hESCs中，ERK1/2的磷酸化也显著减少，ERK1/2是蜕膜化的关键因素。众所周知，子宫内膜异位症患者的hESCs表现出蜕膜功能受损，P4-PR信号轴的失调与包括不孕症和子宫内膜异位症在内的多种子宫内膜疾病有关。因此，这些结果表明CREB3L1是小鼠和人类蜕膜形成所必需的，并可能以一种P4依赖的方式与子宫内膜异位症的发病有关。
Endometriosis is a major cause of infertility and pelvic pain, affecting more than 10% of reproductive-aged women. Progesterone resistance has been observed in the endometrium of women with this disease, as evidenced by alterations in progesterone-responsive gene and protein expression. cAMP-Response Element-Binding 3-like protein 1 (Creb3l1) has previously been identified as a progesterone receptor (PR) target gene in mouse uterus via high density DNA microarray analysis. However, CREB3L1 function has not been studied in the context of endometriosis and uterine biology. In this study, we validated progesterone (P4) regulation of Creb3l1 in the uteri of wild-type and progesterone receptor knockout (PRKO) mice. Furthermore, we observed that CREB3L1 expression was significantly higher in secretory phase human endometrium compared to proliferative phase and that CREB3L1 expression was significantly decreased in the endometrium of women with endometriosis. Lastly, by transfecting CREB3L1 siRNA into cultured human endometrial stromal cells (hESCs) prior to hormonal induction of in vitro decidualization, we showed that CREB3L1 is required for the decidualization process. Interestingly, phosphorylation of ERK1/2, critical factor for decidualization, was also significantly reduced in CREB3L1-silenced hESCs. It is known that hESCs from patients with endometriosis show impaired decidualization and that dysregulation of the P4-PR signaling axis is linked to a variety of endometrial diseases including infertility and endometriosis. Therefore, these results suggest that CREB3L1 is required for decidualization in mice and humans and may be linked to the pathogenesis of endometriosis in a P4-dependent manner.