Epithelial-mesenchymal transition enhances response to oncolytic herpesviral therapy through nectin-1 Academic Article uri icon

Overview

MeSH Major

  • Cell Adhesion Molecules
  • Epithelial-Mesenchymal Transition
  • Herpesvirus 1, Human
  • Neoplasms
  • Oncolytic Viruses

abstract

  • Cancers exhibiting epithelial-mesenchymal transition (EMT) are associated with aggressive behavior and increased metastatic potential. Therapies that are able to target EMT would have significant clinical value. Nectin-1 is a cell surface herpes simplex virus type 1 (HSV-1) receptor that also forms a component of intercellular adherens junctions, which are typically disrupted in EMT. To explore relationships between HSV-1 sensitivity and EMT, we generated cell lines with a stable EMT phenotype from human follicular thyroid cancer (WRO82-1) through E-cadherin silencing with short hairpin RNA (shEcadWRO). HSV-1 viral attachment and gene expression were both enhanced in shEcadWRO as compared with shControl. Immunoblotting and immunostaining revealed enhanced nectin-1 expression by shEcadWRO. Receptor-blocking assays demonstrated that increased herpesviral entry into shEcadWRO as compared with shControl was mediated predominantly through nectin-1. Colocalization of green fluorescent protein-tagged HSV-1 and tdTomato-tagged nectin-1 confirmed an increase in viral attachment to nectin-1 in shEcadWRO. Cell viability assays demonstrated increased susceptibility of shEcadWRO to HSV-1 oncolysis, and a murine flank tumor model showed significantly enhanced regression of shEcadWRO tumors in response to oncolytic HSV-1 as compared with control tumors. A separate model of EMT induction through transforming growth factor-β stimulation confirmed enhanced HSV-1 susceptibility in Panc1 cells. These results demonstrate that the process of EMT leads to increased herpesviral susceptibility through enhanced cell surface nectin-1 expression, suggesting that cancers exhibiting EMT may be naturally sensitive targets for herpesviral therapy.

publication date

  • June 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4064738

Digital Object Identifier (DOI)

  • 10.1089/hum.2013.177

PubMed ID

  • 24568312

Additional Document Info

start page

  • 539

end page

  • 51

volume

  • 25

number

  • 6