Efficient Epstein-Barr Virus Progeny Production Mediated by Cancer-Derived LMP1 and Virally-Encoded microRNAs

Misako Yajima; Mamiko Miyata; Kazufumi Ikuta; Yasuhisa Hasegawa; Chitose Oneyama; Teru Kanda

doi:10.3390/microorganisms7050119

Efficient Epstein-Barr Virus Progeny Production Mediated by Cancer-Derived LMP1 and Virally-Encoded microRNAs

Microorganisms. 2019 Apr 30;7(5):119. doi: 10.3390/microorganisms7050119.

Authors

Misako Yajima¹, Mamiko Miyata², Kazufumi Ikuta³, Yasuhisa Hasegawa^{4

5}, Chitose Oneyama⁶, Teru Kanda^{7

8}

Affiliations

¹ Division of Microbiology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 983-8536, Japan. yajima@tohoku-mpu.ac.jp.
² Division of Cancer Cell Regulation, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan. mmiyata@aichi-cc.jp.
³ Division of Microbiology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 983-8536, Japan. ikutak@tohoku-mpu.ac.jp.
⁴ Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan. hasegawa@murakami.asahi-u.ac.jp.
⁵ Department of Head and Neck Surgery, Asahi University Hospital, Gifu 500-8523, Japan. hasegawa@murakami.asahi-u.ac.jp.
⁶ Division of Cancer Cell Regulation, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan. coneyama@aichi-cc.jp.
⁷ Division of Microbiology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 983-8536, Japan. tkanda@tohoku-mpu.ac.jp.
⁸ Division of Cancer Cell Regulation, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan. tkanda@tohoku-mpu.ac.jp.

Abstract

Epstein-Barr virus (EBV) genomes, particularly their latent genes, are heterogeneous among strains. The heterogeneity of EBV-encoded latent membrane protein 1 (LMP1) raises the question of whether there are functional differences between LMP1 expressed by cancer-associated EBV and that by non-cancerous strains. Here, we used bacterial artificial chromosome (BAC)-cloned EBV genomes retaining all virally encoded microRNA (miRNA) genes to investigate the functions of cancer-derived LMP1 in the context of the EBV genome. HEK293 cells were stably transfected with EBV-BAC clone DNAs encoding either nasopharyngeal carcinoma (NPC)-derived CAO-LMP1 (LMP1_CAO) or LMP1 from a prototype B95-8 strain of EBV (LMP1_B95-8). When an EBV-BAC clone DNA encoding LMP1_CAO was stably transfected into HEK293 cells, it generated many more stable transformants than the control clone encoding LMP1_B95-8. Furthermore, stably transfected HEK293 cells exhibited highly efficient production of progeny virus. Importantly, deletion of the clustered viral miRNA genes compromised the ability to produce progeny viruses. These results indicate that cancer-derived LMP1 and viral miRNAs together are necessary for efficient production of progeny virus, and that the resulting increase in efficiency contributes to EBV-mediated epithelial carcinogenesis.

Keywords: BART; Epstein-Barr virus; LMP1; Nasopharyngeal carcinoma; microRNA.

Abstract

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