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Abstract
Pre-eclampsia is a pregnancy-related disease that may cause maternal, neonatal and fetal morbidity and mortality and exists in 3–5% of pregnancies worldwide. The discovery of dysregulated microRNAs and their roles in placental development has provided a new avenue for elucidating the mechanism involved in this pregnancy-specific disorder. Here, the roles of human miR-181a-5p, a microRNA that is increased in both the plasma and placenta of severe pre-eclamptic patients, in invasion and migration of trophoblasts were investigated. Ectopic-expression of miR-181a-5p impaired the invasion and migration of HTR-8/SVneo cells, whereas miR-181a-5p inhibition had the opposite effects. IGF2BP2, which harbors a highly conserved miR-181a-5p-binding site within its 3ʹ-UTR, was identified to be directly inhibited by miR-181a-5p. Moreover, siRNAs targeting IGF2BP2 imitated the effects of overexpressed miR-181a-5p on HTR-8/SVneo cell invasion and migration, whereas restoring IGF2BP2 expression by overexpressing a plasmid encoding IGF2BP2 partially reversed the studied inhibitory functions of miR-181a-5p. Thus, we demonstrated here that miR-181a-5p suppresses the invasion and migration of cytotrophoblasts, and its inhibitory effects were at least partially mediated by the suppression of IGF2BP2 expression, thus shedding new light on the roles of miR-181a-5p in the pathogenesis of severe pre-eclampsia.
Highlights
Normal proliferation/differentiation of human placental trophoblasts contributes to the proper function of the placenta
Abnormal trophoblasts invasion/ migration caused by dysregulated differentiation of trophoblast cells contributes to PE development
We subsequently tested the invasion/migration capacities of the above three trophoblasts lines and found that the JEG-3 cells, which had the highest miR-181a-5p expression, had the weakest invasion and migration abilities, about 10fold lower than those of HTR-8/SVneo cells, which had the lowest miR-181a-5p expression; JAR cells had a slightly, but not significantly, lower capacities of invasion and migration compared to HTR-8/SVneo cells (Fig. 1c)
Summary
Normal proliferation/differentiation of human placental trophoblasts contributes to the proper function of the placenta. Dysregulated differentiation of trophoblast cells causes abnormal trophoblasts invasion and syncytialization and leads to pregnancy-related diseases including preeclampsia (PE)[1]. An imbalance of proangiogenic and antiangiogenic factors in circulation, including decreased placental growth factor (PlGF), as well as increased endoglin and fms-related tyrosine kinase 1 (FLT1) in soluble form, were implied to have a critical pathogenic role in PE3, the mechanisms involved remain largely unknown. Human miRNAs are highly expressed in the placenta[5] and are substantially altered in the placenta from patients complicated with pregnancy-related diseases, such as PE6–8. MiRNAs in circulation have been suggested as promising biomarkers of pregnancy-related diseases, providing new diagnostic and therapeutic options during pregnancy[9]. In our Official journal of the Cell Death Differentiation Association
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