title: EBV-miR-BHRF1-2 targets PRDM1/Blimp1: potential role in EBV lymphomagenesis.
abstract: PRDM1/Blimp1, a master regulator of B-cell terminal differentiation, has been identified as a tumor suppressor gene in aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL). It has been shown in DLBCL and Hodgkin lymphoma that PRDM1 is downregulated by cellular microRNAs. In this study, we identify the Epstein-Barr virus (EBV) microRNA (miRNA), EBV-miR-BHRF1-2, as a viral miRNA regulator of PRDM1. EBV-miR-BHRF1-2 repressed luciferase reporter activity by specific interaction with the seed region within the PRDM1 3' untranslated region. EBV-miR-BHRF1-2 inhibition upregulated PRDM1 protein expression in lymphoblastoid cell lines (LCL), supporting a role of miR-BHRF1-2 in PRDM1 downregulation in vivo. Discordance of PRDM1 messenger RNA and protein expressions is associated with high EBV-miR-BHRF1-2 levels in LCLs and primary post-transplant EBV-positive DLBCL. Enforced expression of PRDM1-induced apoptosis and cell cycle arrest in LCL cells. Inhibition of EBV-miR-BHRF1-2 negatively regulates cell cycle and decreases expression of SCARNA20, a small nucleolar RNA that is also downregulated by PRDM1 overexpression. The interaction between EBV-miR-BHRF1-2 and PRDM1 may be one of the mechanisms by which EBV-miR-BHRF1-2 promotes EBV lymphomagenesis. Our results support the potential of EBV-miR-BHRF1-2 as a therapeutic target in EBV-associated lymphoma.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Nie
authors.affiliation: Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Redmond
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: O
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Knowles
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Tam
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D001665:Binding Sites; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D016612:Paraffin Embedding; D000074462:Positive Regulatory Domain I-Binding Factor 1; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020537:RNA, Small Nucleolar / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016707:Tissue Fixation; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C083278:BHRF1 protein, Human herpesvirus 4; D035683:MicroRNAs; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D020537:RNA, Small Nucleolar; D012097:Repressor Proteins; D014764:Viral Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1