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Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Hiroshi Higuchi, Natsuko Yamakawa, Ken-Ichi Imadome, Takashi Yahata, Ryutaro Kotaki, Jun Ogata, Masatoshi Kakizaki, Koji Fujita, Jun Lu, Kazuaki Yokoyama, Kazuki Okuyama, Ai Sato, Masako Takamatsu, Natsumi Kurosaki, Syakira Mohamad Alba, Azran Azhim, Ryouichi Horie, Toshiki Watanabe, Toshio Kitamura, Kiyoshi Ando, Takao Kashiwagi, Toshimitsu Matsui, Akinao Okamoto, Hiroshi Handa, Masahiko Kuroda, Naoya Nakamura and Ai Kotani

Key Points

  • EBV-coding miRNAs are transferred from infected into noninfected cells by exosome to regulate the function for the tumorigenesis.

  • Production of EBV-coding miRNAs will be an excellent diagnostic marker to separate patients with EBV+ diffuse large B-cell lymphoma into 2 groups.

Abstract

Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin’s lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBV-encoded RNA. We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-α, and arginase 1, suggesting the immune regulatory role of BART miRNAs. The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma. These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV+ B-cell lymphoma.

  • Submitted July 5, 2017.
  • Accepted April 5, 2018.
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