The EBV-Encoded Oncoprotein, LMP1, Induces an Epithelial-to-Mesenchymal Transition (EMT) via Its CTAR1 Domain through Integrin-Mediated ERK-MAPK Signalling

Research output: Contribution to journalArticlepeer-review

Authors

  • Mhairi A. Morris
  • Louise Laverick
  • Alexandra M. Davis
  • Samantha O'Neill
  • Liam Wood
  • Jack Wright
  • Lawrence S. Young

Colleges, School and Institutes

External organisations

  • Loughborough University
  • Department of Medicine, The Royal Melbourne Hospital, University of Melbourne
  • De Montfort University
  • Warwick Medical School, Gibbet Hill Campus, University of Warwick

Abstract

The Epstein⁻Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) oncogene can induce profound effects on epithelial growth and differentiation including many of the features of the epithelial-to-mesenchymal transition (EMT). To better characterise these effects, we used the well-defined Madin Darby Canine Kidney (MDCK) epithelial cell model and found that LMP1 expression in these cells induces EMT as defined by characteristic morphological changes accompanied by loss of E-cadherin, desmosomal cadherin and tight junction protein expression. The induction of the EMT phenotype required a functional CTAR1 domain of LMP1 and studies using pharmacological inhibitors revealed contributions from signalling pathways commonly induced by integrin⁻ligand interactions: extracellular signal-regulated kinases/mitogen-activated protein kinases (ERK-MAPK), PI3-Kinase and tyrosine kinases, but not transforming growth factor beta (TGFβ). More detailed analysis implicated the CTAR1-mediated induction of Slug and Twist in LMP1-induced EMT. A key role for β1 integrin signalling in LMP1-mediated ERK-MAPK and focal adhesion kianse (FAK) phosphorylation was observed, and β1 integrin activation was found to enhance LMP1-induced cell viability and survival. These findings support an important role for LMP1 in disease pathogenesis through transcriptional reprogramming that enhances tumour cell survival and leads to a more invasive, metastatic phenotype.

Details

Original languageEnglish
Article number130
JournalCancers
Volume10
Issue number5
Publication statusPublished - 1 May 2018

Keywords

  • EBV , LMP1 , NPC , EMT-MAPK , PI3-Kinase , Src family kinase , β1 integrins