Rac1/β-Catenin Signalling Pathway Contributes to Trophoblast Cell Invasion by Targeting Snail and MMP9

Abstract

Background/Aims: Preeclampsia is an idiopathic and serious complication during gestation in which placental trophoblast cells differentiate into several functional subtypes, including highly invasive extravillous trophoblasts (EVTs). Although the cause and pathogenesis of preeclampsia have remained unclear, numerous studies have suggested that the inadequacy of EVT invasion leads to imperfect uterine spiral artery remodelling, which plays a crucial role in the development of preeclampsia. Rac1, or Ras-related C3 botulinum toxin substrate 1, was found to be a key regulator of the migration, invasion uand apoptosis of various tumour cells. Because EVTs share similar invasive and migratory biological behaviours with malignant cells, this study aimed to determine whether the Rac1 signalling pathway affects trophoblast invasion and is thus involved in the pathogenesis of preeclampsia. Methods: We measured the activity of Rac1 and its downstream targets, β-catenin, Snail and MMP9 in placental tissues from patients experiencing a normal pregnancy and those with preeclampsia. Furthermore, we treated HTR-8/SVneo cells with a shRNA Rac1 vector and the β-catenin inhibitor IWP-2 and explored Rac1 signalling pathway activation as well as the effects of Snail and β-catenin on trophoblast invasion. Results: In placental samples from patients experiencing a normal pregnancy and those with preeclampsia, active Rac1 levels and MMP9 protein and mRNA levels were significantly decreased in term pregnancy samples compared to early pregnancy samples. Lower levels were found in preeclampsia samples than in normal term pregnancy samples, and these levels significantly declined in severe preeclampsia samples compared with mild preeclampsia samples. Further analyses demonstrated that both Rac1 shRNA and the β-catenin inhibitor significantly suppressed MMP9 and Snail activation in trophoblasts, thus impairing trophoblast invasion. Notably, silencing Rac1 down-regulated the expression of β-catenin in HTR-8/SVneo cells, demonstrating that β-catenin is a downstream effector of Rac1 in trophoblast invasion. Conclusion: Our data suggest that Rac1-mediated activation of β-catenin might regulate Snail and MMP9 expression subsequently promoting trophoblast invasion in pregnancy.

AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia

“…In this study, we provide evidence that, hypoxia or AICAR treatment significantly increased ROS production in HTR8/SVneo cells, while inhibition of FA β-oxidation totally diminished AICAR promoted ROS production. MMPs are known important for trophoblast invasion [52], although an inhibitory effect of AMPK on MMPs has recently been reported in endothelial progenitor cells and in human umbilical vein endothelial cells [53,54], the present study is the first to demonstrate that AMPK inhibits MMP2 in trophoblast, probably by promoting ROS generation from FA β-oxidation.…”

Down-Regulation of Neuropathy Target Esterase in Preeclampsia Placenta Inhibits Human Trophoblast Cell Invasion via Modulating MMP-9 Levels

“…Among members of MMP family, MMP-2 and MMP-9 were suggested to play an important role in the regulation of trophoblast invasion [31, 32]. Our results showed that reduction of NTE markedly inhibited the production of MMP-9 of HTR-8/SVneo Cells, which was in correspondence with the change of trophoblast cells migration and invasion.…”

Association of dysfunctional synapse defective 1 (SYDE1) with restricted fetal growth - SYDE1 regulates placental cell migration and invasion

“…Rac1, Cdc42, and ROCK are involved in prostaglandin E 2 -stimulated trophoblast cell migration, and RhoGDI2 inhibits trophoblast cell migration by suppression of Rac1 activity [21][22][23]. Decreased Rac1 activities have been observed in pre-eclamptic placentas and genetic ablation of mouse Rock2 leads to placental dysfunction and IUGR [24][25][26].…”