title: EBV-encoded RNA via TLR3 induces inflammation in nasopharyngeal carcinoma.
abstract: Pathogen-induced inflammation has been one of the intensive research areas in carcinogenesis. EBV encoded RNAs (EBERs) have been suggested to play roles in anti-apoptosis and growth-promotion in lymphoid and immune disorders. However, pathological roles of EBERs in solid tumors of epithelia origin remain to be elucidated. Given their characteristic dsRNA structures, recent studies provided evidences for the activation of some pattern recognition receptors (PRR) by EBERs, which is fundamental in the process of pathogenesis. Here, we show that EBERs induce inflammatory response in nasopharyngeal carcinoma (NPC) cells through Toll-like receptor 3 (TLR3), mainly featured by high level of TNFα production. Interestingly, EBERs and EBV latent membrane protein 1 (LMP1) form a positive regulatory loop with NF-κB as a key node that amplifies the inflammatory signals in EBV infected epithelial cells. We demonstrate in vivo that EBERs can interact with TLR3 and induce tumor cells to produce cytokines in B16 synergetic tumor and human NPC xenograft models, in which macrophages are recruited and activated, leading to a favorable microenvironment for solid tumor growth. Lastly, we verify a positive association between EBER and TNFα levels in NPC clinical samples and the combination of EBER and TNFα expressions provides a predictor of poor survival of NPC patients. In conclusion, EBERs play a pivotal role in inflammation-to-oncogenesis transition in NPC development.
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 410008.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 410008.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 410008.
authors.forename: Shiyue
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 410008.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Beijing, China 100193.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 410008.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 410008.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 410008.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 410008.|Cancer Research Institute, Central South University, Changsha, China 410008.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 410008.
authors.forename: Lun-Quan
authors.initials: LQ
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D002277:Carcinoma; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D020031:Epstein-Barr Virus Infections / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism*; D009368:Neoplasm Transplantation; D012330:RNA, Double-Stranded / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D016896:Treatment Outcome; D020298:U937 Cells; D014763:Viral Matrix Proteins / Q000378:metabolism
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D012367:RNA, Viral; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014763:Viral Matrix Proteins
keywords: EBV encoded RNAs (EBERs); TLR3; inflammation; nasopharyngeal carcinoma