title: Modulation of LMP1 protein expression by EBV-encoded microRNAs.
abstract: Epstein-Barr virus (EBV) was the first human virus found to encode microRNAs (miRNAs), but the function of these miRNAs has been obscure. Nasopharyngeal carcinoma (NPC) is associated with EBV infection, and the EBV-encoded LMP1 is believed to be a key factor in NPC development. However, detection of LMP1 protein in NPC is variable. Here, we report that EBV-encoded BART miRNAs target the 3' UTR of the LMP1 gene and negatively regulate LMP1 protein expression. These miRNAs also modulate LMP1-induced NF-kappaB signaling and alleviate the cisplatin sensitivity of LMP1-expressing NPC cells. Consistent with a previous study on the NPC C666-1 cell line and C15 xenograft, we found abundant expression of BART miRNAs in NPC tissues. Furthermore, DNA sequencing revealed that the 3' UTR of LMP1 is highly conserved in NPC-derived EBV isolates. The data provide insight into the discrepancy between LMP1 transcript and protein detection in NPC and highlight the role of the EBV miRNAs in regulating LMP1 downstream signaling to promote cancer development.
authors.affiliation: Viral Oncology Program, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Angela Kwok Fung
authors.initials: AK
authors.lastname: Lo
authors.forename: Ka Fai
authors.initials: KF
authors.lastname: To
authors.forename: Kwok Wai
authors.initials: KW
authors.lastname: Lo
authors.forename: Raymond Wai Ming
authors.initials: RW
authors.lastname: Lung
authors.forename: Jan Wai Ying
authors.initials: JW
authors.lastname: Hui
authors.forename: Gangling
authors.initials: G
authors.lastname: Liao
authors.forename: S Diane
authors.initials: SD
authors.lastname: Hayward
mesh_terms: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015870:Gene Expression; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000821:virology; D012334:RNA, Neoplasm / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D035683:MicroRNAs; D016328:NF-kappa B; D012334:RNA, Neoplasm; D012367:RNA, Viral; D014763:Viral Matrix Proteins; D002945:Cisplatin