Shinozaki-Ushiku Aya, Kunita Akiko, Isogai Maya, Hibiya Takashi, Ushiku Tetsuo, Takada Kenzo, Fukayama Masashi
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Pathology, Yokohama City University Hospital, Yokohama, Japan.
J Virol. 2015 May;89(10):5581-91. doi: 10.1128/JVI.03639-14. Epub 2015 Mar 4.
Epstein-Barr virus (EBV) is one of the major oncogenic viruses and is found in nearly 10% of gastric carcinomas. EBV is known to encode its own microRNAs (miRNAs); however, their roles have not been fully investigated. The present report is the largest series to comprehensively profile the expression of 44 known EBV miRNAs in tissue samples from patients with EBV-associated gastric carcinoma. Several miRNAs were highly expressed in EBV-associated gastric carcinoma, and in silico analysis revealed that the target genes of these EBV miRNAs had functions associated with cancer-related pathways, especially the regulation of apoptosis. Apoptosis was reduced in EBV-associated gastric carcinoma tissue samples, and gastric carcinoma cell lines infected with EBV exhibited downregulation of the proapoptotic protein Bid (the BH3-interacting domain death agonist), a member of the Bcl-2 family. The luciferase activity of the reporter vector containing the 3' untranslated region of BID was inhibited by an ebv-miR-BART4-5p mimic in gastric cancer cell lines. Transfection of an ebv-miR-BART4-5p mimic reduced Bid expression in EBV-negative cell lines, leading to reduced apoptosis under serum deprivation. The inhibition of ebv-miR-BART4-5p expression was associated with partial recovery of Bid levels in EBV-positive cell lines. The results demonstrated the antiapoptotic role of EBV miRNA via regulation of Bid expression in EBV-associated gastric carcinoma. These findings provide novel insights in the roles of EBV miRNAs in gastric carcinogenesis, which would be a potential therapeutic target.
This report is the largest series to comprehensively profile the expression of 44 known EBV miRNAs in clinical samples from EBV-associated gastric carcinoma patients. Of the EBV miRNAs, ebv-miR-BART4-5p plays an important role in gastric carcinogenesis via regulation of apoptosis.
爱泼斯坦-巴尔病毒（EBV）是主要的致癌病毒之一，在近10%的胃癌中可检测到。已知EBV可编码自身的微小RNA（miRNA）；然而，它们的作用尚未得到充分研究。本报告是对EBV相关胃癌患者组织样本中44种已知EBV miRNA表达进行全面分析的最大样本系列。几种miRNA在EBV相关胃癌中高表达，计算机分析显示这些EBV miRNA的靶基因具有与癌症相关途径相关的功能，尤其是对细胞凋亡的调控。EBV相关胃癌组织样本中的细胞凋亡减少，感染EBV的胃癌细胞系中促凋亡蛋白Bid（BH3相互作用结构域死亡激动剂，Bcl-2家族成员）表达下调。在胃癌细胞系中，含有BID 3'非翻译区的报告载体的荧光素酶活性被ebv-miR-BART4-5p模拟物抑制。转染ebv-miR-BART4-5p模拟物可降低EBV阴性细胞系中的Bid表达，导致血清剥夺条件下细胞凋亡减少。抑制ebv-miR-BART4-5p表达与EBV阳性细胞系中Bid水平的部分恢复相关。结果表明EBV miRNA通过调控EBV相关胃癌中Bid的表达发挥抗凋亡作用。这些发现为EBV miRNA在胃癌发生中的作用提供了新的见解，这可能是一个潜在的治疗靶点。
本报告是对EBV相关胃癌患者临床样本中44种已知EBV miRNA表达进行全面分析的最大样本系列。在EBV miRNA中，ebv-miR-BART4-5p通过调控细胞凋亡在胃癌发生中起重要作用。
