Dysfunction of extravillous trophoblasts (EVTs) might cause early pregnancy failure by interfering with embryo implantation and/or placentation. We previously reported that the villus miR-3074-5p expression level was increased, whereas the peripheral level of GDF15, a predict target gene of miR-3074-5p, was decreased in recurrent miscarriages (RM) patients, and miR-3074-5p could enhance apoptosis but reduce invasion of human extravillous trophoblast cells (EVTs). The aim of this study was to further explore roles of miR-3074-5p/GDF15 pathway in regulation of EVTs function. It was validated that GDF15 was not the direct target of miR-3074-5p, whereas EIF2S1, an upstream regulator of GDF15 maturation and secretion, was the direct target of miR-3074-5p. The villus expression levels of GDF15 and EIF2S1 were significantly decreased in RM patients. Knockdown of GDF15 expression presented inhibitory effects on proliferation, migration, and invasion of HTR8/SVneo cells. Up-regulated miR-3074-5p expression led to the significant decreased GDF15 expression in HTR8/SVneo cells, and this effect could be efficiently reversed by the overexpression of EIF2S1. Meanwhile, the suppressive effects of miR-3074-5p on proliferation, migration, and invasion of HTR8/SVneo cells could be intercepted by the treatment of recombinant human GDF15 protein. Collectively, these data suggested that miR-3074-5p could reduce GDF15 production via targeting inhibition of EIF2S1 expression, and the deficiency in GDF15 function might lead to the early pregnancy loss by attenuating proliferation and invasion of EVTs.
Keywords: EIF2S1; Extravillous trophoblasts; GDF15; Recurrent miscarriage; miR-3074-5p.
© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.