Epstein-Barr virus latent antigens EBNA3C and EBNA1 modulate epithelial to mesenchymal transition of cancer cells associated with tumor metastasis.

Epithelial-mesenchymal transition is an important mechanism in cancer invasiveness and metastasis. We had previously reported that cancer cells expressing Epstein-Barr virus (EBV) latent viral antigens EBV nuclear antigen EBNA3C and/ or EBNA1 showed higher motility and migration potential and had a propensity for increased metastases when tested in nude mice model. We now show that both EBNA3C and EBNA1 can modulate cellular pathways critical for epithelial to mesenchymal transition of cancer cells. Our data confirms that presence of EBNA3C or EBNA1 result in upregulation of transcriptional repressor Slug and Snail, upregulation of intermediate filament of mesenchymal origin vimentin, upregulation of transcription factor TCF8/ZEB1, downregulation as well as disruption of tight junction zona occludens protein ZO-1, downregulation of cell adhesion molecule E-cadherin, and nuclear translocation of β-catenin. We further show that the primary tumors as well as metastasized lesions derived from EBV antigen-expressing cancer cells in nude mice model display EMT markers expression pattern suggesting their greater propensity to mesenchymal transition.