Abstract
Background: EBV-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer with EBV latency infection. EBV microRNAs, especially rightward transcript (BART) microRNAs, play key roles in the tumor growth of EBVaGC. However, the effects of EBV-miR-BART19-3p in EBVaGC remain largely unknown. Methods: EBV-miR-BART19-3p was detected by qRT-PCR in EBER in situ hybridization positive gastric carcinoma tissues. CCK8, Colony formation, EdU and Flow cytometry were conducted in gastric cancer cells with overexpression and knockdown of EBV-miR-BART19-3p compared to the negative control, respectively. Tumor xenografts were conducted in vivo. GADD45B was screened by RNA sequencing and dual-luciferase reporter assays implemented with transfecting EBV-miR-BART19-3p antagomir. Proteins were confirmed by Western blotting. Results: EBV-miR-BART19-3p was highly expressed in EBVaGC and promoted the proliferation of EBV-associated gastric cancer cells in vitro and accelerated xenograft tumor growth in vivo. Knockdown of EBV-miR-BART19-3p induced cell cycle G2/M phase arrest in AGS EBV cells. Molecularly, EBV-miR-BART19-3p directly targets the 3'-UTR of growth arrest and DNA damage-inducing protein Beta (GADD45B) mRNA and downregulates its protein expression, which consequently reduced cell cycle G2/M phase arrest. Reconstitution of GADD45B can rescue the proliferation phenotype caused by EBV-miR-BART19-3p in EBVaGC cells. Conclusions: Our study indicated Epstein-Barr Virus MicroRNA BART19-3p played an oncogenic role by a novel mechanism of inhibiting GADD45B in EBVaGC, which provides new insights and might be a potential therapeutic strategy for EBVaGC patients.