cAMP-Response Element-Binding 3-Like Protein 1 (CREB3L1) is Required for Decidualization and its Expression is Decreased in Women with Endometriosis

Abstract

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.

Progesterone Receptor Signaling in Uterine Myometrial Physiology and Preterm Birth

“…Once activated by regulated intramembrane proteolysis, CREB3L1 translocates to the nucleus and exerts genomic actions (Mellor et al, 2013; Murakami et al, 2009). CREB3L1 also acts downstream of PGR to promote ERK signaling for stromal cell decidualization (Ahn et al, 2016). In human uteri, detection of CREB3L1 protein is reported in both epithelial and stromal compartments of endometrium with the strongest expression in the decidual cells at the late secretory stage when the P4 signaling is prominent (Ahn et al, 2016).…”

“…CREB3L1 also acts downstream of PGR to promote ERK signaling for stromal cell decidualization (Ahn et al, 2016). In human uteri, detection of CREB3L1 protein is reported in both epithelial and stromal compartments of endometrium with the strongest expression in the decidual cells at the late secretory stage when the P4 signaling is prominent (Ahn et al, 2016). Although it is not clear whether CREB3L1 is expressed in the myometrium, its mRNA and protein can be detected in various smooth muscle tissues including bladder, stomach and intestine.…”

“…Although it is not clear whether CREB3L1 is expressed in the myometrium, its mRNA and protein can be detected in various smooth muscle tissues including bladder, stomach and intestine. Based on the mouse model, endometrial CREB3L1 expression depends on PGR mediated P4 signaling through mechanisms yet to be identified (Ahn et al, 2016). Functionally, CREB3L1 is required for the decidualization process as evidenced by the failure of decidualization and reduced expression of decidualization marker genes in human endometrial stromal cells after knocking down the CREB3L1 in vitro (Ahn et al, 2016).…”

“…Based on the mouse model, endometrial CREB3L1 expression depends on PGR mediated P4 signaling through mechanisms yet to be identified (Ahn et al, 2016). Functionally, CREB3L1 is required for the decidualization process as evidenced by the failure of decidualization and reduced expression of decidualization marker genes in human endometrial stromal cells after knocking down the CREB3L1 in vitro (Ahn et al, 2016). Decidual cells exhibit distinct features compared with stromal cells they derived from, including larger cell size, enlarged and dilated rough ER, increased in size of the Golgi complexes and increased secretion of prolactin and IGFBP-1 (Lane et al, 1994).…”

“…Moreover, ER stress is associated with fetal growth restriction and endometriosis (Ahn et al, 2016; Lian et al, 2011; Yung et al, 2008). These findings are significant because ER stress has been linked to numerus environmental insults (Kitamura, 2013) and pregnant women are exposed to various environmental stimulations over the course of pregnancy.…”