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
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
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E-钙粘蛋白作为人滋养层细胞侵袭行为的负调节因子，可被环孢菌素 A 通过表皮生长因子/细胞外信号调节蛋白激酶信号通路下调。
DOI：
10.1095/biolreprod.110.083402
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发表时间：
2010-09-01
影响因子：
3.6
通讯作者：
Li, Da-Jin
中科院分区：
文献类型：
--
作者：
Zhao, Hong-Bo;Wang, Can;Li, Da-Jin
我们以前的研究已经证明环孢菌素A（CsA）促进人类早期妊娠滋养层细胞的侵袭性。在本研究中，我们进一步研究了负责改善CsA诱导的人滋养层细胞侵袭力的细胞内信号通路。我们发现，CsA下调E-cadherin在人原代培养的滋养层细胞和绒毛膜癌细胞系JEG-3的转录和翻译。细胞外信号调节蛋白激酶（ERK）抑制剂U 0126可抑制CsA诱导的JEG-3细胞转录抑制因子SNAI 2（又称Slug）的表达，恢复CsA抑制的E-cadherin表达。我们进一步证明，CsA可以增强JEG-3细胞中表皮生长因子（EGF）刺激的表皮生长因子受体（EGFR）酪氨酸磷酸化，而EGFR酪氨酸激酶抑制剂AG 1478抑制EGFR酪氨酸磷酸化，可以消除CsA通过ERK信号通路对E-钙粘蛋白的下调。E-cadherin的表达与JEG-3细胞的侵袭力呈负相关，CsA可逆转E-cadherin过表达导致的JEG-3细胞侵袭力下降。综上所述，CsA可能通过EGFR/ERK信号通路降低E-cadherin的表达，从而促进滋养层细胞侵袭力的增强。
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.