E-Cadherin, as a Negative Regulator of Invasive Behavior of Human Trophoblast Cells, Is Down-Regulated by Cyclosporin A Via Epidermal Growth Factor/Extracellular Signal-Regulated Protein Kinase Signaling Pathway1

Abstract

Our previous study has demonstrated cyclosporin A (CsA) promotes the invasiveness of human first-trimester trophoblast cells. In the present study, we further investigated the intracellular signaling pathway responsible for the improvements in CsA-induced invasiveness of human trophoblast cells. We showed that CsA down-regulated E-cadherin transcription and translation in human primary cultured trophoblast cells and choriocarcinoma cell line JEG-3. U0126, an inhibitor of extracellular signal-regulated protein kinase (ERK), attenuated the CsA-induced transcriptional repressor SNAI2 (also called Slug) expression and restored E-cadherin expression inhibited by CsA in JEG-3 cells. We further demonstrated that CsA amplified epidermal growth factor (EGF)-stimulated EGF receptor (EGFR) tyrosine phosphorylation in JEG-3 cells, and inhibition of EGFR tyrosine phosphorylation by AG1478, an EGFR tyrosine kinase inhibitor, abolished the down-regulation of E-cadherin by CsA through ERK signaling pathway. Moreover, our data showed that E-cadherin expression was negatively correlated to the invasiveness of JEG-3 cells, and CsA could reverse the decreased invasiveness of JEG-3 cells that resulted from E-cadherin overexpression. In conclusion, these observations indicate that CsA may decrease E-cadherin expression via EGFR/ERK signaling pathway and, ultimately, contribute to the invasiveness improvement of human trophoblast cells.

Glucocorticoid exposure in early placentation induces preeclampsia in rats via interfering trophoblast development

“…ERK is essential to regulate trophoblasts differentiation (Daoud et al, 2005). Its activation has been shown to increase the expression of the transcriptional repressors SNAI1 and SNAI2, which in turn down-regulates E-cad (Barberà et al, 2004;Conacci-Sorrell et al, 2003;Zhao et al, 2010). We showed here that ERK was involved in the proliferation, migration, invasion and EMT of HPT-8 cells, while Dex inhibited the proliferation, migration and invasion via reducing ERK activity as well as upregulated E-cad via blocking ERK-SNAI2 cascade.…”

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

“…65 Floridon et al, 66 reported a transient down regulation of E-cadherin expression in migratory and invasive EVT that was restored when trophoblasts aggregated in the decidua to form giant cells, and in the vessel wall after completion of trophoblast migration and invasion. In vitro evidence demonstrated that knock-down of E-cadherin significantly increased invasiveness of the EVT cell line JEG-3 56 and of isolated second trimester trophoblast cells. 65 This evidence suggests E-cadherin is important in the maintenance of an epithelial phenotype in trophoblasts, and reduced E-cadherin expression is associated with trophoblasts acquiring a migration and/or invasion potential.…”

“…54,55 Few studies have examined possible functions of SLUG in placental development. Cyclosporin A, an immunosuppressive agent, promotes invasion of the choriocarcinoma-derived JEG-3 trophoblasts through upregulating SLUG and downregulating E-cadherin, 56 which implicates SLUG in trophoblast regulation. Moreover, trophoblast cells cultured with fibroblast growth factor-4 increased the expression of SLUG and downregulated E-cadherin, which resulted in hyper-invasion of the extracellular matrix.…”

Upregulation of Slug expression by cyclosporine A contributes to the pathogenesis of gingival overgrowth

“…Previously, CsA was found to increase the expression of Slug protein in human choriocarcinoma cell line JEG-3 cells. 23 CsA was also found to increase Slug gene and protein expression in human HK2 renal tubular cells. 24 Taken together, induction of Slug expression by CsA is not cell type specific.…”