CUL4A enhances human trophoblast migration and is associated with pre-eclampsia

We previously found that cullin 4A (CUL4A) is able to promote trophoblast invasion. However, the role of CUL4A in other trophoblast behavior such as migration and the association with pregnancy disorder remains unclear. In this study, Immunostaining revealed that CUL4A was relatively lowly expressed in placentas from pre-eclampsia patients compared with the normal controls. Spiral arteries and inadequate trophoblast migration remodeling result in poor placental perfusion, which mediated maternal injury and may lead to pre-eclampsia. To confirm CUL4A's function on trophoblast migration, we employed human villous explants culture and trophoblast cell line HTR-8/SVneo migration and invasion assay. According to our data, knocking-down CUL4A expression inhibited villous explant's outgrowth significantly in vitro, and down-regulated migration of HTR8/SVneo cells (P<0.01). This effect might be due to reduced matrix metalloproteinases activities, whereas the apoptosis and proliferation of trophoblast cells were not affected. Moreover, CUL4A siRNA increased the levels of both tissue inhibitors of MMPs (TIMP)-1 and -2 significantly. These results suggested that CUL4A may play an essential role in trophoblast cells' migration and dysregulation of CUL4A may be associated with pre-eclampsia.