CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial-mesenchymal transition. (28th August 2018)

• Record Type: Journal Article
• Authors: Ma, Yanbin; Zhang, Haofeng; Xiong, Chaoliang; Liu, Zheng; Xu, Qingji; Feng, Jing; Zhang, Jun; Wang, Zhaoqing; Yan, Xiyun
• Is Part Of: Cancer letters. Volume 430(2018)
• Page Start: 201
• Page End: 214
• Publication Date: 2018-08-28
• Subjects: E-cadherin epithelial cadherin -- N-cadherin neuronal cadherin -- EMT epithelial-mesenchymal transition -- EMT-TF EMT transcriptional factor -- TGF-β transforming growth factor-β -- BMP bone morphogenetic protein -- MEF mouse embryonic fibroblast -- WT wild type -- KO knockout -- OE overexpression -- ERK extracellular regulated protein kinase -- STAT3 signal transducers and activators of transcription -- MAPKs mitogen activated protein kinase -- FGF fibroblast growth factor -- VEGF vascular endothelial growth factor -- PDGF platelet-derived growth factor -- R-SMAD receptor-activated SMAD -- IHC immunohistochemistry; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.05.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Cadherin switch is an initiating factor of epithelial-mesenchymal transition (EMT) and is intimately correlated with cancer metastatic potential; however, its underlying mechanisms remain unclear. Here, using a transforming growth factor-β (TGF-β)-induced EMT model, we provide explicit evidence that CD146, with elevated expression and activity in a variety of cancers, is a key factor involved in the cadherin switch. We show that CD146 can be induced by TGF-β signaling. Moreover, CD146 expression is positively correlated with the activation levels of STAT3/Twist and ERK pathways. Transcriptional response of the CD146/STAT3/Twist cascade inhibits E-cadherin expression, whereas the CD146/ERK cascade enhances N-cadherin expression. CD146 overexpression also significantly promotes EMT in both mouse embryonic fibroblasts (MEFs) and ovarian cancer cells. Clinically, ovarian cancer patients with detectable CD146 expression had a significantly lower survival rate than that of patients without CD146 expression. Furthermore, CD146-deficient MEFs exhibited decreased motility as a result of reversion in this cadherin switch, strongly suggesting that targeting CD146 is a potential strategy for cancer treatment. Therefore, CD146-mediated regulation of the E-cadherin-to-N-cadherin switch provides an insight into the general mechanisms of EMT as well as cancer metastasis. Highlights: CD146 can be induced by TGF-β signaling. CD146 promote the activation of STAT3 and ERK. CD146/STAT3/Twist cascade inhibits E-cadherin expression. CD146/ERK cascade enhances N-cadherin expression. CD146 promotes EMT and decreases survival rate of ovarian cancer patients.