Activation of WNT/CTNNB1/TCF7L2 in Epstein-Barr virus–positive gastric cancer regulates epithelial mesenchymal transition

Abstract

Gastric cancer (GC) is the fifth most frequently diagnosed malignant tumour and the third leading cause of cancer-related death. EBV infection is one of the major causes of GC, accounting for approximately 10% of GC cases. Studies revealed that EBV infection could induce malignancy through multilevel mechanisms, including epigenetics state alterations, miRNA regulations, etc. However, it is poorly understood if EBV positive GC has any characteristic oncogenic singling activation. By comparing the transcriptomic of EB positive and negative cell lines, TCGA GC samples, and GC single cells, we identified that canonical WNT signalling is commonly activated in EBV positive GC. Next, we proved that the WNT activation is crucial for the invasiveness of the GC via regulating epithelial-mesenchymal transition (EMT) gene expressions. Then we confirmed that the WNT signalling activation in EBV + GC is through the WNT/CTNNB1 (β-catenin)/TCF7L2 axis with the expression of TCF7L2 indicating worse outcome and more metastasis in EBV+ GCs. Finally, we found that KLF5 is potentially involved as a cooperative transcription factor in the early phase of the EMT process through single-cell pseudotime analysis.