AQP3 influences the development of recurrent spontaneous abortion by regulating trophoblast proliferation and migration via the AQP3/IGF2BP1/PI3K/AKT signaling pathway

Abstract

Abstract Background Reduced trophoblast migration and invasion contributes markedly to recurrent spontaneous abortion (RSA). Aquaporin 3 (AQP3) is a key protein necessary for trophoblast migration and invasion in the fetal–maternal crosstalk during early pregnancy. However, the involvement of AQP3 in RSA remains unknown. Here, the molecular mechanisms acting upstream and downstream of AQP3 and modulatory effects on trophoblast migration and invasion were examined. Methods AQP3 expression was detected in the villi of patients with RSA. The molecular mechanisms whereby AQP3 regulates the migration and invasion of human extravillous trophoblasts (HTR-8/SVneo cells), including the role of the PI3K/AKT signaling pathway and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), were investigated. Results AQP3 expression was lower in the villi of patients with RSA than in the controls. Key PI3K/AKT signaling pathway kinase expression levels were elevated after AQP3 overexpression (OE); the opposite effects occurred after AQP3 knockdown. PI3K/AKT signaling inhibition by LY294002 partially reversed trophoblast migration and invasion and AQP3 OE-mediated PI3K/AKT activation. IGF2BP1 knockdown reduced AQP3 mRNA stability and impaired trophoblast migration and invasion; IGF2BP1 OE exerted the opposite effects. AQP3 mRNA bound to the IGF2BP1 protein, and the m6A-modified AQP3 was significantly enriched in HTR-8/SVneo cells. Conclusions IGF2BP1 detects and binds to AQP3 mRNA, enhancing its stability and activating the PI3K/AKT pathway, thereby affecting the migration and invasion of HTR-8/SVneo cells. These findings indicate a new fundamental mechanism for treating RSA.