HOXC8 alleviates high glucose-triggered damage of trophoblast cells during gestational diabetes mellitus via activating TGFβ1-mediated Notch1 pathway.

Abstract

Gestational diabetes mellitus (GDM) is an increasingly frequent disease occurred during pregnancy. HOXC8 has been disclosed to take part in the regulation of cancers. Additionally, the HOXC8 expression was dramatically decreased in the placenta of pre-eclampsia patients, but its expression and function have not been investigated in GDM. In this work, it was demonstrated that the mRNA and protein expression of HOXC8 was lower in GDM placenta tissues and GDM cell model. In addition, HOXC8 facilitated trophoblast cell proliferation and weakened trophoblast cell mitochondrial apoptosis. HOXC8 enhanced trophoblast cell migration and angiogenesis. Moreover, HOXC8 activated the TGFβ1-mediated Notch1 signaling pathway. Results showed that the mRNA and protein expressions of TGFβ1 and Notch1 were both lower in the GDM group than that in the NP group. Besides, there were positive correlations among HOXC8, TGFβ1 and Notch1. Inhibition of TGFβ1 (SB202190 treatment) reversed the effects of HOXC8 on trophoblast cells through modulating cell proliferation, mitochondrial apoptosis, migration and angiogenesis. At last, through in vivo experiments, it was identified that HOXC8 relieved GDM symptoms in vivo. In conclusion, HOXC8 alleviated HG-stimulated damage of trophoblast cells during GDM through activating TGFβ1-mediated Notch1 pathway. This discovery may provide a novel and useful bio-target for GDM treatment.