EBV 编码的 miR-BART12-3p 下调 GSDMB 抑制胃癌细胞中杀伤淋巴细胞介导的细胞焦亡

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer (GC) with characteristic clinicopathological and molecular features. EBVaGC exhibits a more extensive lymphocyte infiltration than EBV-negative counterparts, and expresses a range of EBV encoded viral products.

However, the interactions between EBV-positive GC cells and immune cells within the tumor microenvironment are not well understood.

Herein we found that EBV downregulates GSDMB, an executive molecule of pyroptosis, in EBV-positive GC cells and enables these cells to escape GSDMB cleavage-induced pyroptosis by NK cells and cytotoxic T lymphocytes. The pyroptosis is mainly executed through the full length GSDMB isoform (GSDMBiso3) in GC cells.

We further found EBV-encoded miR-BART12-3p targets the GSDMB 3'-UTR to downregulate its expression in GC cells. Inhibition of miR-BART12-3p enhances antitumor efficacy of NK cells against EBV-positive GC cells by triggering GSDMB cleavage-induced pyroptosis, as demonstrated both in vitro and in vivo.

In conclusion, this study elucidates the molecular mechanism by which EBV downregulates GSDMB to evade immune cell killing, and provides a rationale for combining killer lymphocyte-based therapies with a miR-BART12-3p inhibitor for the treatment of EBVaGC.