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. Epub 2018 May 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD146 Antigen / genetics
  • CD146 Antigen / metabolism
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Epithelial-Mesenchymal Transition*
  • Female
  • Fibroblasts
  • Gene Knockout Techniques
  • Humans
  • Mice
  • Middle Aged
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology*
  • Ovary / pathology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Survival Rate
  • Transforming Growth Factor beta / metabolism
  • Twist-Related Protein 1 / metabolism

Substances

  • CD146 Antigen
  • Cadherins
  • MCAM protein, human
  • Mcam protein, mouse
  • Nuclear Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TWIST1 protein, human
  • Transforming Growth Factor beta
  • Twist-Related Protein 1