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[摘要]：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 20 alpha-hydroxysteroid dehydrogenase (20 alpha-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 20 alpha-HSD in laboring myometrium from mouse and human. Notably, overexpression of miR-200a in cultured human myometrial cells (hTERT-HM) suppressed STAT5b and increased 20a-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 20 alpha-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 20 alpha-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. |
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