Epstein-Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer
Epstein-Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer
复制标题
Epstein-Barr病毒miR-BART3-3p通过调节胃癌衰老途径促进肿瘤发生
DOI：
10.1074/jbc.ra118.006853
复制
发表时间：
2019-03-29
影响因子：
4.8
通讯作者：
Ma, Jian
中科院分区：
文献类型：
--
作者：
Wang, Jia;Zheng, Xiang;Ma, Jian
EB病毒相关性胃癌（Epstein-Barr virus-associated gastric cancer，EBVaGC）约占所有胃癌病例的10%，具有独特的病理和分子特征。EBV编码大量microRNA，其积极参与EBV相关肿瘤的发展。在此，我们报告EBV-miR-BART 3 - 3 p（BART 3 - 3 p）在体外和体内促进胃癌细胞生长。此外，BART 3 - 3 p抑制癌基因（RAS（G12 V））或化疗（伊立替康）诱导的胃癌细胞衰老。LMP 1和EB病毒编码的EBNA 3C也有报道具有抗衰老作用;然而，在EBVaGC标本中，LMP 1表达非常低，EBNA 3C不表达。BART 3 - 3 p通过改变衰老相关分泌表型（SASP）抑制胃癌细胞衰老，并抑制肿瘤中自然杀伤细胞和巨噬细胞的浸润。从机制上讲，BART 3 - 3 p直接靶向肿瘤抑制基因TP 53，并引起p53下游靶点p21的下调。来自临床EBVaGC样品的分析也显示BART 3 - 3 p和TP 53表达之间的负相关性。众所周知，突变的癌基因RAS（G12 V）或化疗药物可以诱导衰老，在这里，我们表明RAS（G12 V）和化疗药物也可以诱导EBV阳性胃癌细胞中BART 3 - 3 p的表达，形成反馈回路，使EBVaGC衰老保持在低水平。我们的研究结果表明，虽然TP 53在EBVaGC中很少突变，但其表达受到精细调控，因此EBV编码的BART 3 - 3 p可能通过抑制胃癌细胞的衰老而发挥重要作用。
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.