Significant up-regulation of Toll-like receptor (TLR) signaling pathway in Epstein-Barr virus-associated gastric cancer.

Objectives: Epstein-Barr virus (EBV) associated gastric cancer (EBVaGC) represents a distinct subtype of gastric carcinoma clinically characterized by low frequency of lymph node metastasis and better prognosis as compared to the EBV-negative gastric cancer (EBVnGC). Differential expression analysis of the transcriptome from tumor tissues revealed frequent involvement of immune genes which emphasizes the exclusive significance of immune response in EBVaGC patients. Considering the reported over-expression of toll-like receptor (TLR) genes in EBV infection and giving the crucial roles of TLRs in the innate immune system, we assumed that the entire TLR signaling pathway could have been differentially regulated in EBVaGC.

Methods: We tested our hypothesis by performing a differential expression analysis of the whole TLR signaling pathway using gene set enrichment test.

Results: A self-matched test detected a significant upregulation of the TLR signaling pathway in tumor as compared with non-tumor gastric tissues of EBVaGCs (P = 4×10^-3) but no significant differential regulation of the pathway in EBVnGCs. A comparison of tumor gastric tissue in EBVaGCs versus non-tumor gastric tissue in EBVnGCs showed an even more significant upregulation of the pathway with a high enrichment of overexpressed genes (P = 2.5×10^-4).

Conclusions: Briefly, this study revealed a distinct pattern of activation of the TLR signaling pathway in EBVaGCs which can be seen as a specific feature of molecular pathology in the disease. This feature characterizes the disease as a distinct subtype of gastric cancer in oncogenesis which can be linked to its clinical manifestation and prognosis to motivate improved treatment strategies for both EBVaGC and EBVnGC patients.