The Epstein-Barr Virus-Encoded EBNA1 Protein Activates the Bone Morphogenic Protein (BMP) Signalling Pathway to Promote Carcinoma Cell Migration

Hannah E Bridgewater, Kathryn L Date, John D O'Neil, Chunfang Hu, John R Arrand, Christopher W Dawson, Lawrence S Young

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6 Citations (Scopus)
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Abstract

The Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) protein is expressed in all virus-associated malignancies, where it performs an essential role in the maintenance, replication and transcription of the EBV genome. In recent years, it has become apparent that EBNA1 can also influence cellular gene transcription. Here, we demonstrate that EBNA1 is able to stimulate the expression of the Transforming growth factor-beta (TGFβ) superfamily member, bone morphogenic protein 2 (BMP2), with consequential activation of the BMP signalling pathway in carcinoma cell lines. We show that BMP pathway activation is associated with an increase in the migratory capacity of carcinoma cells, an effect that can be ablated by the BMP antagonist, Noggin. Gene expression profiling of authentic EBV-positive nasopharyngeal carcinoma (NPC) tumours revealed the consistent presence of BMP ligands, established BMP pathway effectors and putative target genes, constituting a prominent BMP "signature" in this virus-associated cancer. Our findings show that EBNA1 is the major viral-encoded protein responsible for activating the BMP signalling pathway in carcinoma cells and supports a role for this pathway in promoting cell migration and possibly, metastatic spread.

Original languageEnglish
Article number594
Number of pages23
JournalPathogens (Basel, Switzerland)
Volume9
Issue number7
DOIs
Publication statusPublished - 21 Jul 2020
Externally publishedYes

Bibliographical note

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Funder

Funding Information:
Funding: This research was funded by Cancer Research UK (grant number C198/A3916) awarded to CWD, JRA and LSY, and a University PhD scholarship awarded to KLD by the College of Medical and Dental Sciences (CMDS), University of Birmingham Medical School.

Funding Information:
This research was funded by Cancer Research UK (grant number C198/A3916) awarded to CWD, JRA and LSY, and a University PhD scholarship awarded to KLD by the College of Medical and Dental Sciences (CMDS), University of Birmingham Medical School. Acknowledgments: We are grateful to Ms Sonia Maia for providing technical assistance. We are grateful to Peter ten Dijke, Leiden University Medical Centre for providing the BRE-luciferase reporter construct and Jaap Middeldorp, Amsterdam, UMC, for providing the K67 anti-EBNA1 antibody.

Keywords

  • Bone morphogenic protein
  • Epstein-Barr nuclear antigen 1
  • Epstein-Barr virus
  • Undifferentiated nasopharyngeal carcinoma

ASJC Scopus subject areas

  • Immunology and Allergy
  • Molecular Biology
  • Immunology and Microbiology(all)
  • Microbiology (medical)
  • Infectious Diseases

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