Antagonistic Roles of miR-199a-3p/miR-214 and the miR-200 Family in the Regulation of Uterine Contractility During Pregnancy and Labor
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Progesterone (P4) and estradiol-17β (E2) play critical and opposing roles in regulating myometrial quiescence and contractility during pregnancy and labor (Kamel et al., 2010). While these contrasting hormonal effects are likely mediated via differential regulation of inflammatory and contractile genes, the underlying mechanisms remain incompletely understood. Recently, we discovered that miR-200 family members, miR-200b and miR-429, and their target, transcription factor ZEB1, serve as P4/progesterone receptor (PR)-mediated regulators of uterine quiescence during pregnancy (Renthal et al., 2010). In the present study, we identified a novel role for another miR-200 family member, miR-200a, to enhance local metabolism of P4 in myometrium and, thus, decrease PR function during the progression towards labor (Williams et. al., 2012a). This occurs via miR-200a repression of signal transducer and activator of transcription (STAT)5b, a transcriptional repressor of the P4-metabolizing enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD). We observed that miR-200a expression increased and STAT5b expression coordinately decreased in myometrium of mice as they progressed to labor and in laboring myometrium from pregnant women. These changes were associated with a dramatic increase in expression and activity of 20α-HSD in laboring myometrium from mouse and human. In a progesterone-withdrawal mouse model of preterm labor, preterm labor was associated with increased miR-200a, decreased STAT5b and enhanced 20α-HSD expression. In other studies, we also found that levels of the clustered miRNAs, miR-199a-3p and miR-214, were significantly decreased in laboring myometrium of pregnant mice and humans and in a inflammatory mouse model of preterm labor, while the miR-199a-3p/miR-214 target, cyclooxygenase-2 (COX-2), a critical enzyme in synthesis of pro-inflammatory prostaglandins, was coordinately increased (Williams et al., 2012b). The physiological relevance of the labor-associated increase in miR-199a-3p/214 expression was highlighted by the finding that overexpression of miR-199a-3p and miR-214 in cultured human myometrial cells inhibited COX-2 protein and blocked TNF-α-induced myometrial cell contractility. Notably, estrogen and P4 treatment of ovariectomized mice have opposing effects on uterine miR-199a-3p/214 expression that were mediated by ZEB1. Whereas, P4 stimulated ZEB1 and upregulated miR-199a/214 expression in mouse and human myometrium (Renthal et al., 2010), estrogen had an opposing inhibitory effect. Notably, ZEB1/2 inhibit miR-200 family expression. Together, our findings point to the key pivotal roles of myometrial ZEB1 and its miRNA targets as a hormonally-controlled regulators of inflammatory and contractile gene expression in the pregnant uterus during term and preterm labor.