Zeb1 for RCP-induced oral cancer cell invasion and its suppression by resveratrol

Exp Mol Med. 2020 Jul;52(7):1152-1163. doi: 10.1038/s12276-020-0474-1. Epub 2020 Jul 30.


Rab coupling protein (RCP) is upregulated in head and neck squamous cell carcinoma (HNSCC) and is correlated with the progression and survival of patients. However, the role of RCP in one of the aggressive types of HNSCC, oral squamous cell carcinoma (OSCC), remains elusive. In the present study, we identified the important role of Zeb1 in RCP-induced OSCC epithelial-to-mesenchymal transition (EMT) and invasion. RCP induces Zeb1 expression, and silencing Zeb1 expression significantly inhibits RCP-induced OSCC invasion. In addition, Zeb1 upregulates MT1-MMP expression to promote OSCC EMT and invasion. Furthermore, we observed that the β1 integrin/EGFR/β-catenin signaling cascade mediates RCP-induced Zeb1 expression to promote OSCC invasion. Notably, we provide evidence that resveratrol (REV) strongly inhibits RCP-induced Zeb1 expression through blocking β1 integrin endosome recycling and EGFR activation, leading to suppression of RCP-induced OSCC invasion, demonstrating the important role of RCP in OSCC invasion and its reversion by REV. Collectively, the present study provides evidence for the first time that RCP aggravates OSCC invasion through increasing Zeb1 expression and subsequently upregulating MT1-MMP expression and that this process is reversed by REV, providing novel biomarkers and indicating the therapeutic potential of REV in OSCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition* / drug effects
  • ErbB Receptors / metabolism
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology*
  • Humans
  • Integrin beta1 / metabolism
  • Matrix Metalloproteinase 14 / metabolism
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Neoplasm Invasiveness
  • Resveratrol / pharmacology*
  • Signal Transduction / drug effects
  • Squamous Cell Carcinoma of Head and Neck / metabolism*
  • Squamous Cell Carcinoma of Head and Neck / pathology*
  • Transcription Factor 4 / metabolism
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Integrin beta1
  • Membrane Proteins
  • RAB11FIP1 protein, human
  • TCF4 protein, human
  • Transcription Factor 4
  • Zinc Finger E-box-Binding Homeobox 1
  • ErbB Receptors
  • Matrix Metalloproteinase 14
  • Resveratrol