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

Koriand'r C. Williams, Nora E. Renthal, Jennifer C. Condon, Robert D. Gerard, Carole R. Mendelson

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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 (P4)-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 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. 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 P4, 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 P4 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.

Original languageEnglish (US)
Pages (from-to)7529-7534
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number19
DOIs
StatePublished - May 8 2012

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20-Hydroxysteroid Dehydrogenases
Premature Obstetric Labor
Progesterone Receptors
MicroRNAs
Myometrium
Uterus
Messenger RNA
Progesterone
Pregnant Women
Pregnancy
Enzymes

ASJC Scopus subject areas

  • General

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MicroRNA-200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor. / Williams, Koriand'r C.; Renthal, Nora E.; Condon, Jennifer C.; Gerard, Robert D.; Mendelson, Carole R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 19, 08.05.2012, p. 7529-7534.

Research output: Contribution to journalArticle

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