Targeting Exosomal EBV-LMP1 Transfer and miR-203 Expression via the NF-κB Pathway: The Therapeutic Role of Aspirin in NPC

Lielian Zuo; Yan Xie; Jinyong Tang; Shuyu Xin; Lingzhi Liu; Siwei Zhang; Qijia Yan; Fanxiu Zhu; Jianhong Lu

Molecular Therapy: Nucleic Acids (Sep 2019)

Targeting Exosomal EBV-LMP1 Transfer and miR-203 Expression via the NF-κB Pathway: The Therapeutic Role of Aspirin in NPC

Lielian Zuo,
Yan Xie,
Jinyong Tang,
Shuyu Xin,
Lingzhi Liu,
Siwei Zhang,
Qijia Yan,
Fanxiu Zhu,
Jianhong Lu

Affiliations

Lielian Zuo: NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, Hunan, China; Institute of Neuroscience, Medical College, University of South China, Hengyang 421001, Hunan, China
Yan Xie: NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, Hunan, China
Jinyong Tang: Department of Otolaryngology-Head and Neck Surgery, the First People’s Hospital of Chenzhou, Chenzhou 423000, Hunan, China
Shuyu Xin: NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, Hunan, China
Lingzhi Liu: NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, Hunan, China
Siwei Zhang: NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, Hunan, China
Qijia Yan: NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China
Fanxiu Zhu: NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, Hunan, China; Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA
Jianhong Lu: NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya Hospital, Central South University, Changsha 410080, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, Hunan, China; Corresponding author: Jianhong Lu, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Microbiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410078, Hunan, China.

Journal volume & issue: Vol. 17
pp. 175 – 184

Abstract

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Nasopharyngeal carcinoma (NPC) is an invasive head-and-neck tumor with Epstein-Barr virus (EBV) as an important etiological cause. The EBV oncoprotein Latent membrane protein 1 (LMP1) can be trafficked into exosomes with unclear roles, and this trafficking is a potential problem in NPC control. MicroRNA-203 (miR-203) was found by us to be downregulated by LMP1, and it functions as a tumor suppressor in NPC. In this study, aspirin reversed the epithelial-mesenchymal transition (EMT) by promoting miR-203 expression in cells, and, remarkably, it repressed exosomal LMP1 (exo-LMP1) secretion from EBV-positive cells. Nuclear factor κB (NF-κB) activation was required for the exo-LMP1 production. The exo-LMP1 uptake influenced the EMT potential of EBV-negative recipient NPC cells. The exo-LMP1 level was upregulated in clinical NPC plasma samples. Aspirin treatment observably inhibited NPC lung metastasis in nude mice. The study revealed that aspirin is a promising drug for NPC therapy via its targeting of exo-LMP1 transfer and the regulatory effect of LMP1 on miR-203 expression. EBV can regulate its own tumorigenesis via the LMP1/NF-κB/exo-LMP1 axis, opening a new avenue for understanding the pathogenesis of this tumor virus. Our study also provides a rationale for the use of exo-LMP1 or exosomal miR-203 (exo-miR203) in EBV-targeted therapy by aspirin in invasive NPC. Keywords: aspirin, exosomes, Epstein-Barr virus, Latent membrane protein 1, microRNA-203, nasopharyngeal carcinoma

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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