MicroRNA-200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor

Abstract

During pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) activity, but labor is facilitated by a series of events that impair PR function. Previously, we discovered that miR-200 family members serve as progesterone (P 4 )-modulated activators of contraction-associated genes in the pregnant uterus. In this study, we identified a unique role for miR-200a to enhance the local metabolism of P 4 in myometrium and, thus, decrease PR function during the progression toward labor. miR-200a exerts this action by direct repression of STAT5b, a transcriptional repressor of the P 4 -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. Notably, overexpression of miR-200a in cultured human myometrial cells (hTERT-HM) suppressed STAT5b and increased 20α-HSD mRNA levels. In uterine tissues of ovariectomized mice injected with P 4 , miR-200 expression was significantly decreased, STAT5b expression was up-regulated, and 20α-HSD mRNA was decreased, but in 15 d postcoitum pregnant mice injected with the PR antagonist RU486, preterm labor was associated with increased miR-200a, decreased STAT5b, and enhanced 20α-HSD expression. Taken together, these findings implicate miR-200a as an important regulator of increased local P 4 metabolism in the pregnant uterus near term and provide insight into the importance of miR-200s in the decline in PR function leading to labor.

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

“…Therefore, P 4 levels during human pregnancy in the context of the etiology of preterm birth and parturition timing remain unsettled. A recent report shows that microRNA-200a via STAT5b increases local metabolism of P 4 by increasing the expression of AKR1C1 in immortalized human myometrial cells in culture (63). Another report shows AKR1C1 expression in human deciduae (64).…”

Prevention of preterm birth: Harnessing science to address the global epidemic

“…Near term, increased miR-200 expression silences ZEB1 and ZEB2, resulting in further up-regulation of miR-200 members. Furthermore, miR-200 members also silence signal transducer and activator of transcription 5B (STAT5B), which is known to repress 20α-hydroxysteroid dehydrogenase (20a-HSD), a progesterone-metabolizing enzyme (30). This leads to increased breakdown of progesterone (P4) to inactive products, reduced local concentration of progesterone, lower PR-dependent up-regulation of ZEB1/2, and enhanced expression of CAPs.…”

MicroRNAs, immune cells and pregnancy

“…We are only beginning to discover the roles of miRNAs in reproduction. miRNAs have been implicated in endometrial receptivity, [34][35][36] implantation, 37-42 labor [43][44][45][46][47] and even spontaneous fetal loss in the pig. 48,49 In the uterus, most of the physiological changes occurring over the estrous/menstrual cycle and during pregnancy are driven by the ovarian hormones.…”