Down-regulation of DKK1 and Wnt1/β-catenin pathway by increased homeobox B7 resulted in cell differentiation suppression of intrauterine fetal growth retardation in human placenta

This study aimed to test the influence of homeobox B7 (HoxB7) on the proliferation, invasion, and migration of human trophoblast cells and to reveal the down-regulation of HoxB7 on the transcriptional suppression of Dick Kopf-related protein1 (DKK1) and of Cysteine-rich glycosylated wingless protein 1 (Wnt1)/β-catenin in intrauterine fetal growth retardation (FGR). Quantitative measurement of HoxB7, DKK1, Wnt1, and β-catenin was performed in human placentas collected from normal pregnancies and from FGR with quantitative real time PCR (qRT-PCR). Cultured HTR-8/SVneo cells, transfected with a lentiviral plasmid that in-frame expresses human HoxB7 gene, were applied to functional assessment to study the biological impact of HoxB7 gene on DKK1, Wnt1, and β-catenin. Counting Kit-8, Transwell invasion assays, and flow cytometry were applied for the functional measurements. The expression of HoxB7 was significantly increased, and of DKK1, Wnt1, and β-catenin was decreased, in FGR placenta tissues and in HTR-8/SVneo cells. Function studies revealed that overexpression of HoxB7 inhibited proliferation, migration, and invasion in HTR-8/SVneo cells. DKK1, Wnt1, and β-catenin were down-regulated in HTR-8/SVneo cells, inversely correlated with HoxB7 expression. Overexpression of HoxB7 showed a suppressive effect on proliferation, migration, and invasion in the HTR-8/SVneo cells. Our results indicate that HoxB7 inhibited human trophoblast cell differentiation by down-regulating DKK1 expression and that it may affect transcription of Wnt1/β-catenin. The activation of HoxB7 might suppress the cell differentiation in HTR-8/SVneo cell cultures. The Wnt/β-catenin signaling pathway may play a significant role in the pathogenesis of FGR by regulating the invasion and proliferation of trophoblasts.