Epstein-Barr virus-encoded EBNA1 modulates the AP-1 transcription factor pathway in nasopharyngeal carcinoma cells and enhances angiogenesis in vitro

• Published in: Journal of general virology 2008-11, Vol.89 (11), p.2833-2842
• Main Authors: O'Neil, John D, Owen, Thomas J, Wood, Victoria H. J, Date, Kathryn L, Valentine, Robert, Chukwuma, Marilyn B, Arrand, John R, Dawson, Christopher W, Young, Lawrence S
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Biological and medical sciences; Cell Line; Cell Line, Tumor; Epstein-Barr virus; Epstein-Barr Virus Nuclear Antigens - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Genome, Viral; Herpesvirus 4, Human - genetics; Humans; Immunohistochemistry; Interleukin-8 - physiology; Kidney - embryology; Microbiology; Microtubules - pathology; Miscellaneous; Nasopharyngeal Neoplasms - blood supply; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - virology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - virology; Transcription Factor AP-1 - physiology; Vascular Endothelial Growth Factor A - physiology; Virology
• ISSN: 0022-1317; 1465-2099
• DOI: 10.1099/vir.0.2008/003392-0

Cancer Research UK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK Correspondence John D. O'Neil ONeilJD{at}bham.ac.uk The Epstein–Barr virus (EBV)-encoded EBNA1 protein is expressed in all virus-associated tumours, including nasopharyngeal carcinoma (NPC), where it plays an essential role in EBV genome maintenance, replication and transcription. Previous studies suggest that EBNA1 may have additional effects relevant to oncogenesis, including enhancement of cell survival, raising the possibility that EBNA1 may influence cellular gene expression. We have recently demonstrated by gene expression microarray profiling in an NPC cell model that EBNA1 influences the expression of a range of cellular genes, including those involved in transcription, translation and cell signalling. Here, we report for the first time that EBNA1 enhances activity of the AP-1 transcription factor in NPC cells and demonstrate that this is achieved by EBNA1 binding to the promoters of c-Jun and ATF2, enhancing their expression. In addition, we demonstrate elevated expression of the AP-1 targets interleukin 8, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 in response to EBNA1 expression, which enhances microtubule formation in an in vitro angiogenesis assay. Furthermore, we confirm elevation of VEGF and the phosphorylated isoforms of c-Jun and ATF2 in NPC biopsies. These findings implicate EBNA1 in the angiogenic process and suggest that this viral protein might directly contribute to the development and aggressively metastatic nature of NPC. Present address: Laboratory of Cancer Biology, University of Oxford, Room 1501, Women's Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK. Three supplementary figures and a supplementary table are available with the online version of this paper.