Abstract
Epstein Barr Virus (EBV) is a human herpesvirus, and has been reported to be associated with nasopharyngeal carcinoma, gastric carcinoma, Burkitt’s lymphoma and Hodgkin’s lymphoma. In most of the associated tumors, the virus remains in a latently infected state. During latency, EBV expresses Latent Membrane Protein 2A (LMP2A) along with few other genes. We previously showed that LMP2A causes downregulation of HLA-ABC surface expression in EBV associated gastric carcinomas. However, the mechanism that leads to this downregulation remain unclear. We therefore analyzed methylation-mediated regulation of HLA-ABC expression by LMP2A. Interestingly, according to the ‘missing self’ hypothesis, when there is a decrease in HLA-ABC surface expression, expression of NKG2D ligands’ must be upregulated to facilitate killing by Natural Killer (NK) cells. Analysis of NKG2D ligands’ expression, revealed downregulation of MIC-A/B surface expression in response to LMP2A. Furthermore, the role of Unfolded Protein Response (UPR) in the regulation of MIC-A/B surface expression in cells expressing LMP2A was also investigated. Protein Disulfide Isomerase (PDI) mediated inhibition of MIC-A/B surface expression was observed in LMP2A expressing cells. Our current findings provide new insights in LMP2A arbitrated dysregulation of host immune response in epithelial cell carcinomas.
Highlights
Epstein Barr Virus (EBV), γ-human herpes virus, is known to be associated with various malignancies such as Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Nasopharyngeal Carcinoma, Gastric Carcinoma, and Breast Cancer[6,7,8,9]
First we identified the epigenetic regulators with increased expressions in, AGS expressing Latent Membrane Protein 2A (LMP2A) (AGS-LMP2A) through quantitation of mRNA level compared to vector control cells (AGS) using quantitative Real-Time Polymerase chain reaction (PCR) (qRT-PCR)
The surface expression of MIC-A/B was significantly enhanced in AGS-LMP2A cell (Supplementary Fig. 4D) and SNU-719 cell (Supplementary Fig. 4E) upon Forskolin treatment. These results suggest that decreased MIC-A/B surface expression in EBV infected epithelial cell carcinomas is due to activation of Sonic Hedgehog (Shh) pathway
Summary
EBV, γ-human herpes virus, is known to be associated with various malignancies such as Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Nasopharyngeal Carcinoma, Gastric Carcinoma, and Breast Cancer[6,7,8,9]. HLA is reported to present intracellular peptides derived from viral and tumour antigens to the counteracting T-cell receptors, resulting in recognition of virus-infected tumour cells by CTLs. We previously reported decreased HLA-ABC surface expression through EBV latent protein, LMP2A in EBVaGC18,19. NK cell-mediated killing of virus-infected cells requires the expression of the activating receptor, NKG2D (natural killer group[2], member D) on NK cells, NKT cells, and some CTLs. Eight tumour-associated ligands’ are identified for human NKG2D activating receptors which include MIC-A and MIC-B, along with six retinoic acid early transcript-1 proteins ULBPs (ULBP1-6). We investigated that loss of MIC-A/B surface expression was due to PDI This comprehensive analysis of cell surface molecules in EBV associated epithelial cell carcinomas, provides insights into molecular mechanisms by which LMP2A regulates immune evasion
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