Epstein–Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer

Abstract

Epstein-Barr virus-associated gastric cancer (EBVaGC) accounts for about 10% of all gastric cancer cases and has unique pathological and molecular characteristics. EBV encodes a large number of microRNAs, which actively participate in the development of EBV-related tumors. Here, we report that <i>EBV-miR-BART3-3p</i> (BART3-3p) promotes gastric cancer cell growth <i>in vitro</i> and <i>in vivo</i> Moreover, BART3-3p inhibits the senescence of gastric cancer cells induced by an oncogene (RAS^G12V) or chemotherapy (irinotecan). LMP1 and EBNA3C encoded by EBV have also been reported to have antisenescence effects; however, in EBVaGC specimens, LMP1 expression is very low, and EBNA3C is not expressed. BART3-3p inhibits senescence of gastric cancer cells in a nude mouse model and inhibits the infiltration of natural killer cells and macrophages in tumor by altering the senescence-associated secretory phenotype (SASP). Mechanistically, BART3-3p directly targeted the tumor suppressor gene <i>TP53</i> and caused down-regulation of p53's downstream target, p21. Analysis from clinical EBVaGC samples also showed a negative correlation between BART3-3p and <i>TP53</i> expression. It is well known that mutant oncogene RAS^G12V or chemotherapeutic drugs can induce senescence, and here we show that both RAS^G12V and a chemotherapy drug also can induce BART3-3p expression in EBV-positive gastric cancer cells, forming a feedback loop that keeps the EBVaGC senescence at a low level. Our results suggest that, although <i>TP53</i> is seldom mutated in EBVaGC, its expression is finely regulated such that EBV-encoded BART3-3p may play an important role by inhibiting the senescence of gastric cancer cells.