期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 13, 页码 4854-4866出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.006853
关键词
DNA viruses; microRNA (miRNA); cellular senescence; gastric cancer; p53; Epstein-Barr virus; miR-BART3-3p
资金
- National Natural Science Foundation of China [81472694, 81672889, 81672993, 31670171]
- China 111 Project [111-2-12]
- Hunan Province Science and Technology Project [2016JC2035]
- Key Laboratory of Translational Radiation Oncology Hunan Province Open Research Fund Program [2015TP1009]
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 EBV-miR-BART3-3p (BART3-3p) promotes gastric cancer cell growth in vitro and in vivo. 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 TP53 and caused down-regulation of p53's downstream target, p21. Analysis from clinical EBVaGC samples also showed a negative correlation between BART3-3p and TP53 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 TP53 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.
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