WNT5A, [beta]-catenin and SUFU expression patterns, and the significance of microRNA deregulation in placentas with intrauterine growth restriction

Placental insufficiency is a common cause of intrauterine growth restriction (IUGR). It affects ~10% of pregnancies and increases fetal and neonatal morbidity and mortality. Although Wnt and Hh pathways are crucial for embryonic development and placentation, their role in the pathology of IUGR is still not sufficiently explored. The present study analyzed the expression of positive regulators of the Wnt pathway, WNT5A and [beta]-catenin, and the expression of the Hh pathway negative regulator suppressor of fused (SUFU). Immunohistochemical and reverse transcription-quantitative PCR (RT-qPCR) assays were performed on 34 IUGR and 18 placental tissue samples from physiologic singleton-term pregnancies. Epigenetic mechanisms of SUFU gene regulation were also investigated by methylation-specific PCR analysis of its promoter and RT-qPCR analysis of miR-214-3p and miR-378a-5p expression. WNT5A protein expression was higher in endothelial cells of placental villi from IUGR compared with control tissues. That was also the case for [beta]-catenin protein expression in trophoblasts and endothelial cells and SUFU protein expression in trophoblasts from IUGR placentas. The SUFU gene promoter remained unmethylated in all tissue samples, while miR-214-3p and miR-378a-5p were downregulated in IUGR. The present results suggested altered Wnt and Hh signaling in IUGR. DNA methylation did not appear to be a mechanism of SUFU regulation in the pathogenesis of IUGR, but its expression could be regulated by miRNA targeting. Key words: intrauterine growth restriction, placenta, WNT5A, [beta]-catenin, suppressor of fused, Wnt signaling pathway, Hh signaling pathway, DNA methylation, microRNA 214, microRNA 378