Epstein-Barr virus (EBV)-encoded
miRNAs within the BamHI-A rightward transcript (BART) region are abundantly expressed in EBV-associated
gastric cancer (EBVaGC), suggesting that they play roles in
tumorigenesis. However, how these viral
miRNAs contribute to the development of EBVaGC remains largely obscure. In this study, we found that EBV-encoded miR-BART11-3p targets
3' -UTR of
dual-specificity phosphatase 6 (DUSP6)
mRNA to upregulate ERK phosphorylation and downregulate JNK and p38 phosphorylation. By doing so, miR-BART11-3p promotes
gastric cancer (GC) cell proliferation, migration, and invasion in vitro, and facilitates
tumor growth in vivo. Restoration of DUSP6 expression reverses the
tumor-promoting activity of miR-BART11-3p in AGS GC cells. Consistently, knockdown of DUSP6 ablates the antitumor effects of miR-BART11-3p inhibitors in EBV-positive GC cells. Furthermore, blocking ERK phosphorylation with
trametinib inhibited the proliferation, migration, and invasion of miR-BART11-3p-expressing AGS cells. Administration of a miR-BART11-3p
antagomir reduced the growth of EBV-positive xenograft
tumors. Together, these findings reveal a novel mechanism by which EBV dysregulates MAPK pathways through an EBV-encoded
microRNA to promote the development and progression of EBVaGC, which may be harnessed to develop new
therapeutics to treat EBVaGC. IMPORTANCE The Epstein-Barr virus (EBV) is the first human tumor virus found to encode
miRNAs, which within the BART region have been detected abundantly in EBV-associated
gastric cancer (EBVaGC) and play various roles in promoting
tumorigenesis. In our study, we observed that EBV-miR-BART11-3p promotes cell proliferation and induces migration and invasion in GC. Interestingly, we showed that miR-BART11-3p upregulates p-ERK and downregulates p-JNK and p-p38 by directly targeting 3'-UTR of
dual-specificity phosphatase 6 (DUSP6). Restoration of DUSP6 rescues the effects generated by miR-BART11-3p in GC cells, and blocking ERK phosphorylation with
Trametinib augments JNK and p38 phosphorylation and inhibits the effects of miR-BART11-3p-expressing AGS cells, suggesting that miR-BART11-3p promotes cell proliferation, migration, and invasion by modulating DUSP6-MAPK axis in EBVaGC. The findings presented in this study provide new mechanisms into the
tumorigenesis in EBVaGC and new avenues for the development of therapeutic strategies to combat EBVaGC targeting miR-BART11-3p or phospho-ERK.