EBV viral load in tumor tissue from nasopharyngeal biopsy has been shown in our study not related to baseline tumor extensiveness. Even though EBV is presence in almost all nasopharyngeal cancer, the number of virus presence within the cancer cells did not translate into greater or smaller tumor sizes. This finding indicating that EBV virus replication within the host cells does not affect cancer phenotype.
There are evidence suggesting that expression of several EBV viral oncogenic genes are related to cancer development.4,13 These oncogenic proteins are probably the major driver of carcinogenesis, especially the proteins expressed by the latent EBV genes.4 In acute EBV infection, the lytic phase will ensue with expression of lytic genes. After lytic infection the virus will reside and become dormant within the epithelial or lymphocytes by expression of various latent genes. This latent genes such as Latent Membrane Protein 1 (LMP1) and Epstein-Barr nuclear antigen 1 (EBNA-1) expressed in latent phase of EBV infection were found to contribute to cancer development.4
The viral protein LMP1 was associated with inactivation of several important genes such as tumor suppressor genes within the host cells.4,14,15 The LMP1 inactivated tumor suppressor genes for instance Phosphatase and tensin homolog (PTEN) gene through the action of DNA methyltransferase 3b (DNMT3b).15 This DNMT3b resulted in PTEN CpG island methylation.15 Furthermore, the LMP1 expressed by EBV has also been shown to be able to methylate CDH-1 promoter region which eventually silencing E-cadherin gene. The cadherin is cell adhesion molecule in which deficient in this protein will promote cancer cells to easily metastasize.16
The EBNA-1 viral protein was associated with gene methylation process and genomic instability within the host genome.4,14 The gene profiling study has shown that EBNA-1 could bound to promoter sites of many host genes and resulted in upregulation and downregulation of specific genes.17 The presence of EBNA-1 was also related with elevated production of reactive oxygen species (ROS) within the host cells.18 This elevated ROS further increased the likelihood of genomic instability and DNA damage.18 In pre-clinical model, EBNA-1 expression was shown to be strongly associated with tumor growth.19 All these findings indicating that EBNA-1 is required at least in part for tumorigenesis.
Another EBV molecule that is also highly transcribed in latent EBV infection was Epstein-Barr Virus - encoded RNAs (EBER). The EBER is a small segment of RNA molecule that is not expressed into protein, but it plays a major role in facilitating the process of immune escape.4 The EBER can interfere with interferon stimulating gene, thereby blunting the immune response.20 In concert with other EBV viral proteins such as LMP1, the EBV could stimulate recruitment and activation of Treg into tumor microenvironment, therefore stimulating an even more permissive microenvironment for tumor growth.21
Based on all the findings above and the result of our study, the expression of these oncogenic viral genes is probably more likely to correlate with tumor progression rather than presence and the number of EBV virus alone. EBV viral load quantification in tumor tissue was probably useful to assist doubtful diagnosis of nasopharyngeal cancer, especially the endemic type with WHO type 3 histopathology.22 Quantification EBV DNA in tumor cells might not be able to confer valuable prognostic information. However, quantification of viral proteins or RNAs might be able to provide some prognostic clue.