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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Base Sequence
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Binding Sites
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Carcinogenesis / genetics*
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Cell Cycle Checkpoints
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Cell Line, Tumor
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Epstein-Barr Virus Infections / genetics*
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Epstein-Barr Virus Infections / metabolism
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Epstein-Barr Virus Infections / pathology
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Gene Expression Regulation, Neoplastic*
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Herpesvirus 4, Human / genetics
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Herpesvirus 4, Human / pathogenicity
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Host-Pathogen Interactions
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Humans
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Lymphoma, Large B-Cell, Diffuse / genetics*
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Lymphoma, Large B-Cell, Diffuse / pathology
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Molecular Sequence Data
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Paraffin Embedding
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Positive Regulatory Domain I-Binding Factor 1
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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RNA, Small Nucleolar / genetics
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RNA, Small Nucleolar / metabolism
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism
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Signal Transduction
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Tissue Fixation
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Viral Proteins / antagonists & inhibitors
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Viral Proteins / genetics*
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Viral Proteins / metabolism
Substances
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3' Untranslated Regions
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BHRF1 protein, Human herpesvirus 4
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MicroRNAs
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Protein Isoforms
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RNA, Small Interfering
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RNA, Small Nucleolar
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Repressor Proteins
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Viral Proteins
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PRDM1 protein, human
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Positive Regulatory Domain I-Binding Factor 1