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 pathway.
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.
Zhao
Hong-Bo
HB
Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China.
Wang
Can
C
Li
Rui-Xia
RX
Tang
Chuan-Ling
CL
Li
Ming-Qing
MQ
Du
Mei-Rong
MR
Hou
Xiao-Fan
XF
Li
Da-Jin
DJ
D000704:Analysis of Variance; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016572:Cyclosporine / Q000378:metabolism* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D015820:Cadherins; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D016572:Cyclosporine; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases