Farrokhnia, F, Aplin, JD, Westwood, M et al. (1 more author) (2014) MicroRNA regulation of mitogenic signaling networks in the human placenta. Journal of Biological Chemistry, 289 (44). pp. 30404-30416. ISSN 0021-9258
Abstract
Placental cell growth depends on an adaptable combination of an endogenous developmental program and the exogenous influence of maternal growth factors, both of which may be influenced by microRNA (miR)-dependent effects on gene expression. We have previously shown that global miR suppression in placenta accelerates proliferation and enhances levels of growth factor signaling mediators in cytotrophoblast. This study aimed to identify miRs involved in regulating placental growth. An initial array revealed 58 miR species whose expression differs between first trimester, when cytotrophoblast proliferation is rapid, and term, by which time proliferation has slowed. In silico analysis defined potential growth-regulatory miRs; among these, hsa-miR-145, hsa-miR-377, and hsa-let-7a were predicted to target known placental growth genes and were higher at term than in the first trimester, so they were selected for further analysis. Overexpression of miR-377 and let-7a, but not miR-145, in first trimester placental explants significantly reduced basal cytotrophoblast proliferation and expression of ERK and MYC. PCR arrays, in silico analysis, Western blotting, and 3'-UTR luciferase reporter assays revealed targets of miR-145 within the insulin-like growth factor axis. Analysis of proliferation in placental explants overexpressing miR-145 demonstrated its role as a mediator of insulin-like growth factor-induced trophoblast proliferation. These findings identify miR-377 and let-7a in regulation of endogenous cell growth and miR-145 in the placental response to maternal stimulation and will aid the development of therapeutic strategies for problem pregnancies.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Keywords: | Developmental Factor; Gene Regulation; Insulin-like Growth Factor (IGF); MicroRNA (miRNA); Placenta; Proliferation; Reproduction; Trophoblast; Cell Line; Cell Proliferation; Female; Gene Regulatory Networks; Humans; MicroRNAs; Mitosis; Placenta; Pregnancy; Pregnancy Trimester, First; RNA Interference; Signal Transduction; Somatomedins; Transcriptome; Trophoblasts |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Genetics, Health and Therapeutics (LIGHT) > Division of Reproduction & Early Development Research (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 12 Jul 2016 11:17 |
Last Modified: | 08 Nov 2016 18:33 |
Published Version: | http://dx.doi.org/10.1074/jbc.M114.587295 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology |
Identification Number: | 10.1074/jbc.M114.587295 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:83093 |