Blocking the interaction between circTNRC18 and LIN28A promotes trophoblast epithelial–mesenchymal transformation and alleviates preeclampsia

Abstract

Defects in migration and invasion caused by dysregulation of trophoblastic epithelial–mesenchymal transformation (EMT) play a vital role in preeclampsia (PE). We have previously shown that circTNRC18 inhibits the migration and EMT of trophoblasts; however, its role in PE remains unknown. Herein, we demonstrate that circTNRC18 interacts with an RNA-binding protein, lin-28 homolog A (LIN28A), and this interaction is enhanced in PE placental tissue. LIN28A overexpression suppresses circTNRC18-mediated inhibition of trophoblast migration, invasion, and EMT, whereas LIN28A knockdown promotes them. The intracellular distribution of LIN28A is regulated by circTNRC18, where it promotes the expression of insulin-like growth factor II by stabilizing its mRNA. circTNRC18 also promotes complex formation between GATA-binding factor 1 (GATA1) and sine oculis homeobox 1 (SIX1) by inhibiting LIN28A–GATA1 interaction. GATA1–SIX1 promotes transcription of grainyhead-like protein 2 homolog and circTNRC18-mediated regulation of cell migration and invasion. Moreover, blocking circTNRC18–LIN28A interaction with antisense nucleotides alleviates PE in a mouse model of reduced uterine perfusion pressure. Thus, targeting the circTNRC18–LIN28A regulatory axis may be a novel PE treatment method.