Profiling of Virus-Encoded MicroRNAs in Epstein-Barr Virus-Associated Gastric Carcinoma and Their Roles in Gastric Carcinogenesis.
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.


OBJECTIVE
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.
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Aya
A
Shinozaki-Ushiku
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Akiko
A
Kunita
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Maya
M
Isogai
Department of Pathology, Yokohama City University Hospital, Yokohama, Japan.
Takashi
T
Hibiya
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Tetsuo
T
Ushiku
Hokkaido University, Sapporo, Japan.
Kenzo
K
Takada
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan mfukayama-tky@umin.org.
Masashi
M
Fukayama
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics; D001483:Base Sequence; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020031:Epstein-Barr Virus Infections / Q000209:etiology / Q000235:genetics* / Q000821:virology*; D005260:Female; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics*; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics* / Q000821:virology*
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D035683:MicroRNAs; D012367:RNA, Viral