CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial-mesenchymal transition

  • Cancer Lett. 2018 Aug 28;430:201-214. doi: 10.1016/j.canlet.2018.05.016.
Yanbin Ma  1 ,  Haofeng Zhang  2 ,  Chaoliang Xiong  1 ,  Zheng Liu  3 ,  Qingji Xu  1 ,  Jing Feng  3 ,  Jun Zhang  4 ,  Zhaoqing Wang  5 ,  Xiyun Yan  6
Affiliations
  • 1. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2. Obstetrics and Gynecology Medical Center of Severe Cardiovascular Disease of Beijing, Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
  • 3. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 4. Obstetrics and Gynecology Medical Center of Severe Cardiovascular Disease of Beijing, Anzhen Hospital, Capital Medical University, Beijing, 100029, China. Electronic address: [email protected].
  • 5. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. Electronic address: [email protected].
  • 6. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
PMID: 29777784 DOI: 10.1016/j.canlet.2018.05.016
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.

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