MicroRNA Regulation of Mitogenic Signaling Networks in the Human Placenta

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.

Exploration of the regulation and control mechanisms of miR‑145 in trophoblast cell proliferation and invasion

“…Suppressed cell migration and cancer invasion has also been reported, which suggests that miR-145 may function as a tumor suppressor (30). The results of the present study are in accordance with those of a previous study that indicated that miR-145 is a positive regulator of endogenously regulated trophoblast expansion (19). Genes associated with trophoblast invasion include heme oxygenase-1, epidermal growth factor (EGF), VEGF and MUC1 (21,31,32).…”

“…It has been reported that miR-145 may be able to regulate the expression of sex determining region Y-box 2 and influence the proliferation and invasion ability of JAR and JEG-3 cells in the development of human choriocarcinomas (18,19). Mucin (MUC1) is a type 1 transmembrane protein that serves a vital role in trophoblast cell proliferation and migration (20).…”

Influence of gestational diabetes mellitus on human umbilical vein endothelial cell miRNA

“…The miR-let-7 family has also been shown to inhibit oxidized LDL uptake and apoptosis of endothelial cells [36,37]. In the placenta, let-7a has been shown to reduce cytotrophoblast proliferation [38]. Polymorphisms in let-7 have been associated with increased risk of T2DM [39].…”

miR-145 suppresses embryo–epithelial juxtacrine communication at implantation by modulating maternal IGF1R

“…We have recently shown that miR-145 is important in mediating placental growth in humans (Farrokhnia et al, 2014;Forbes et al, 2012). One of the targets of miR-145 is the type-1 insulin-like growth factor receptor (IGF1R) (La Rocca et al, 2009;Law et al, 2012) and IGF1R mRNA has been previously shown to be present in endometrium (Zhou et al, 1994).…”