title: Nasopharyngeal carcinoma progression is mediated by EBER-triggered inflammation via the RIG-I pathway.
abstract: EBERs (EBER1 and EBER2) are suggested to be involved in cellular transformation and tumor growth. Cytoplasmic pattern recognition receptor-RIG-I, which is characterized by the recognition of viral dsRNAs, could efficiently trigger the downstream pathways of innate immunity. Although some previous reports have shown that EBERs and RIG-I associate with hematological malignancies, the role of EBERs-RIG-I signaling in solid tumors remains to be clarified. Here we demonstrate that EBER mediation of the inflammatory response via RIG-I contributes to NPC development in vitro and in vivo. We first verified that the expression level of RIG-I was associated with EBER transcription in a dose-dependent manner in NPC cells and specimens from NPC patients. Furthermore, pro-inflammatory cytokine transcription and release were sharply reduced after RIG-I knockdown compared with the control shRNA group in the presence of EBERs, accompanied by an attenuation of the NF-κB and MAPK signaling pathways. Consequently, the tumor burden was greatly alleviated in the RIG-I knockdown group in a xenograft model. In addition, macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein (MCP-1), which promote the maturation and attraction of tumor-associated macrophages, were stimulated upon the introduction of EBERs, and this upregulation conceivably led to the tumor-promoting subset transition of the macrophages. Taken together, our results reveal that EBERs could promote NPC progression through RIG-I-mediated cancer-related inflammation.
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; The department of pathology of Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Shiyue
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Cancer Research Institute, Central South University, Changsha 410008, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address: gongzhicheng2013@163.com.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address: lunquansun@csu.edu.cn.
authors.forename: Lun-Quan
authors.initials: LQ
authors.lastname: Sun
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma; D002454:Cell Differentiation; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000032:analysis; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; C099537:Epstein-Barr virus encoded RNA 1; C106732:Epstein-Barr virus encoded RNA 2; C494232:IRF3 protein, human; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
keywords: EBV encoded-non-coding RNAs (EBERs); Inflammation; nasopharyngeal carcinoma (NPC); retinoic acid-inducible gene I (RIG-I)