Abstract
Preeclampsia is a pregnancy-specific complication defined as newly onset gestational hypertension and proteinuria. Deficiency in placental development is considered as the predominant cause of preeclampsia. Our previous study found that the expression of miR-518b increased significantly in the preeclamptic placentas, indicating the potential participation of this small RNA in the occurrence of preeclampsia. In this study, data analysis using multiple databases predicted Rap1b as a candidate target of miR-518b. An evident decrease in Rap1b expression was observed in preeclamptic placentas when compared with the control placentas, which was negatively correlated with the level of miR-518b. Based on the data of in situ hybridization and immunohistochemistry showing that Rap1b exhibited similar localization with miR-518b in villous cytotrophoblast cells and column trophoblasts, we further explored their function in regulating trophoblast cell proliferation. In HTR8/SVneo cells, exogenous transfection of miR-518b reduced the expression of Rap1b, and dual-luciferase reporter assay validated Rap1b as the direct target of miR-518b. The small RNA could increase the BrdU incorporation and the ratio of cells at S phase, and enhance the phosphorylation of Raf-1 and ERK1/2. Such growth-promoting effect could be efficiently reversed by Rap1b overexpression. The data indicate that miR-518b can promote trophoblast cell proliferation via Rap1b–Ras–MAPK pathway, and the aberrant upregulation of miR-518b in preeclamptic placenta may contribute to the excessive trophoblast proliferation. The study provides new evidence to further understand the etiology of preeclampsia.
Highlights
Preeclampsia is a complicated pregnancy-associated syndrome featured as newly occurred hypertension and proteinuria after gestational week 20
We examined the association of miR-518b and Rap1b in preeclamptic placenta, and further explored the influence of miR-518b on trophoblast cell proliferation by targeting Rap1b
We previously identified a significant upregulation of miR-518b in severe preeclamptic placentas [13]
Summary
Preeclampsia is a complicated pregnancy-associated syndrome featured as newly occurred hypertension and proteinuria after gestational week 20. It affects 3–5% pregnant women all over the world and has been a major cause of maternal and fetal death [1]. MicroRNAs are small non-coding RNAs composed of 19–22 nucleotides. They can bind the 3′UTR of the targeted mRNA and block the translation or accelerate the degeneration of the mRNA, decreasing the protein production [2]. Placenta is a miRNArich organ, and increasing evidences reveal the important roles of miRNAs in regulating trophoblast cell behaviors. Some miRNAs, such as C19MC, C14MC, and miR-371-3 gene cluster, are expressed in the placenta [3], indicating their unique functions in this organ
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