title: The Epstein-Barr virus-encoded microRNA MiR-BART9 promotes tumor metastasis by targeting E-cadherin in nasopharyngeal carcinoma.
abstract: MicroRNAs (miRNAs) are a family of small RNA molecules that negatively regulate the expression of protein-coding genes and play critical roles in orchestrating diverse cellular processes. This regulatory mechanism is also exploited by viruses to direct their life cycle and evade the host immune system. Epstein-Barr virus (EBV) is an oncogenic virus that is closely associated with multiple human diseases, including nasopharyngeal carcinoma (NPC), which is a highly metastatic type of tumor and is frequently reported in South Asia. Several viral proteins have been found to promote the migration and invasiveness of NPC cells. However, not all tumor tissues express these viral oncoproteins, suggesting that other mechanisms may contribute to the aggressive behavior of NPC tumor cells. A previous sequencing study by our group revealed that the EBV miRNA miR-BART9 was expressed at high levels in all EBV-positive NPC tissues. In the present study, we used gain- and loss-of-function approaches to investigate the effect of miR-BART9 in EBV-negative and EBV-positive NPC cells. We discovered that miR-BART9 promotes the migration and invasiveness of cultured NPC cells. The promigratory activity observed in vitro was manifested as an enhanced metastatic ability in vivo. Computational analysis revealed that miR-BART9 may target E-cadherin, a membrane protein that is pivotal in preserving cell-cell junctions and the epithelial phenotype. Through biochemical assays and functional rescue analysis, we confirmed that miR-BART9 specifically inhibits E-cadherin to induce a mesenchymal-like phenotype and promote the migration of NPC cells. These results indicated that miR-BART9 is a prometastatic viral miRNA and suggested that high levels of miR-BART9 in EBV-positive NPC cells may contribute to the aggressiveness of tumor cells.
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.
authors.forename: Chung-Yuan
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan, Republic of China.
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Yi
authors.affiliation: Department of Otolaryngology, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan, Republic of China.
authors.forename: Kai-Ping
authors.initials: KP
authors.lastname: Chang
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan, Republic of China.
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China ; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan, Republic of China ; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.
authors.forename: Shu-Jen
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China ; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan, Republic of China ; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.
authors.forename: Hua-Chien
authors.initials: HC
authors.lastname: Chen
mesh_terms: D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002277:Carcinoma; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D004854:Herpesvirus 4, Human; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012367:RNA, Viral / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D015820:Cadherins; D035683:MicroRNAs; D012367:RNA, Viral