Elevated glucose levels trigger trophoblast cell invasion dysfunction through enhanced senescence and IGFBP4 signaling pathway.

Gestational diabetes mellitus (GDM) is related to multiple negative pregnancy outcomes such as miscarriage, pre-eclampsia and so on. Cell senescence was considered potential mechanism of GDM. However, the role and mechanism of high glucose and cellular senescence in trophoblast cells are largely unknown. Here, we observed cell senescence and expression of glucose transporter 3 (GLUT3) were up-regulated in GDM placenta. In vitro study confirmed the migration and invasion abilities were impaired in H2O2-induced senescent choriocarcinoma JEG3 cells. Additionally, high glucose triggered senescent phenotype, impaired migration and invasion of senescent JEG3 cells. The expression of GLUT3 was increased in senescent JEG3 cells, and overexpression of GLUT3 induced cell senescence, suggesting a feedback loop between cell senescence and up-regulation of GLUT3. Overexpression of GLUT3 enhanced glucose uptake and lactate accumulation, and decreased migration and invasion of JEG3 cells, mechanically, these processes were dependent on IGFBP4. These data suggest that GLUT3/high glucose induces migration and invasion dysfunction of trophoblast cells, possibly contributing to placental dysfunction of GDM.