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

doi:10.3390/pathogens9070594

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

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

47 Downloads (Pure)

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 language	English
Article number	594
Number of pages	23
Journal	Pathogens (Basel, Switzerland)
Volume	9
Issue number	7
DOIs	https://doi.org/10.3390/pathogens9070594
Publication status	Published - 21 Jul 2020
Externally published	Yes

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.

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.

Funders	Funder number
University of Birmingham
Cancer Research UK	C198/A3916

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

ASJC Scopus subject areas

Immunology and Allergy
Molecular Biology
General Immunology and Microbiology
Microbiology (medical)
Infectious Diseases

Access to Document

10.3390/pathogens9070594Licence: CC BY

PublishedFinal published version, 15.5 MBLicence: CC BY

Cite this

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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.",

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AU - Hu, Chunfang

AU - Arrand, John R

AU - Dawson, Christopher W

AU - Young, Lawrence S

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KW - Epstein-Barr virus

KW - Undifferentiated nasopharyngeal carcinoma

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

Abstract

Bibliographical note

Funder

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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