title: 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.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Koriand'r C
authors.initials: KC
authors.lastname: Williams
authors.forename: Nora E
authors.initials: NE
authors.lastname: Renthal
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Condon
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Carole R
authors.initials: CR
authors.lastname: Mendelson
mesh_terms: D043607:20-alpha-Hydroxysteroid Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007743:Labor, Obstetric / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics*; D015735:Mifepristone / Q000494:pharmacology; D009215:Myometrium / Q000166:cytology / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000235:genetics* / Q000378:metabolism; D010052:Ovariectomy; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D006727:Hormone Antagonists; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D011980:Receptors, Progesterone; D050799:STAT5 Transcription Factor; D015735:Mifepristone; D011374:Progesterone; D043607:20-alpha-Hydroxysteroid Dehydrogenase