Ahn J I, Yoo J-Y, Kim T H, Kim Y I, Ferguson S D, Fazleabas A T, Young S L, Lessey B A, Ahn J Y, Lim J M, Jeong J-W
Laboratory of Stem Cell and Bioevaluation, Major in Biomodulation, Seoul National University, Seoul 151-921, Republic of Korea.
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, College of Human Medicine, 333 Bostwick Avenue NE, Suite 4024, Grand Rapids, MI 49503, USA.
Curr Mol Med. 2016;16(3):276-87. doi: 10.2174/1566524016666160225153659.
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. cAMPResponse 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.
子宫内膜异位症是导致不孕和盆腔疼痛的主要原因，影响超过10%的育龄妇女。在患有这种疾病的女性子宫内膜中已观察到孕激素抵抗，孕激素反应性基因和蛋白质表达的改变证明了这一点。先前通过高密度DNA微阵列分析已确定cAMP反应元件结合3样蛋白1（Creb3l1）是小鼠子宫中的孕激素受体（PR）靶基因。然而，尚未在子宫内膜异位症和子宫生物学背景下研究CREB3L1的功能。在本研究中，我们验证了野生型和孕激素受体敲除（PRKO）小鼠子宫中Creb3l1的孕激素（P4）调节。此外，我们观察到，与增殖期相比，分泌期人子宫内膜中CREB3L1表达显著更高，而子宫内膜异位症女性的子宫内膜中CREB3L1表达显著降低。最后，在体外诱导蜕膜化的激素诱导之前，将CREB3L1 siRNA转染到培养的人子宫内膜基质细胞（hESC）中，我们表明CREB3L1是蜕膜化过程所必需的。有趣的是，在CREB3L1沉默的hESC中，蜕膜化的关键因子ERK1/2的磷酸化也显著降低。已知子宫内膜异位症患者的hESC显示蜕膜化受损，并且P4-PR信号轴的失调与包括不孕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是小鼠和人类蜕膜化所必需的，并且可能以P4依赖的方式与子宫内膜异位症的发病机制相关。
