Chronic inflammation is recognized as a threat factor for cancer progression. Release of inflammatory molecules generates microenvironment which is highly favorable for development of tumor, cancer progression and metastasis. In cases of latent viral infections, generation of such a microenvironment is one of the major predisposing factors related to virus mediated tumorigenesis. Among various inflammatory mediators implicated in pathological process associated with cancer, the cyclooxygenase (COX) and its downstream effector molecules are of greater significance. Though the role of infectious agents in causing inflammation leading to transformation of cells has been more or less well established, however, the mechanism by which inflammation in itself modulates the events in life cycle of infectious agent is not very much clear. This is specifically important for gammaherpesviruses infections where viral life cycle is characterized by prolonged periods of latency when the virus remains hidden, immunologically undetectable and expresses only a very limited set of genes. Therefore, it is important to understand the mechanisms for role of inflammation in virus life cycle and tumorigenesis. This review is an attempt to summarize the latest findings highlighting the significance of COX-2 and its downstream signaling effectors role in life cycle events of gammaherpesviruses leading to progression of cancer.

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, up-regulation 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.

Inflammation is one of the predisposing factors known to be associated with Epstein Barr Virus (EBV) mediated tumorigenesis. However it is not well understood whether inflammation in itself plays a role in regulating the life cycle of this infectious agent. COX-2, a key mediator of the inflammatory processes is frequently over-expressed in EBV positive cancer cells. In various tumours, PGE2 is the principle COX-2 regulated downstream product which exerts its effects on cellular processes through the EP1-4 receptors. In this study, we further elucidated how upregulated COX-2 levels can modulate the events in EBV life cycle related to latency-lytic reactivation. Our data suggest a role for upregulated COX-2 on modulation of EBV latency through its downstream effector PGE2. This study demonstrates a role for increased COX-2 levels in modulation of EBV latency. This is important for understanding the pathogenesis of EBV-associated cancers in people with chronic inflammatory conditions.

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