EBV-miR-BHRF1-2 targets PRDM1/Blimp1: potential role in EBV lymphomagenesis

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 stu...

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Bibliographic Details
Published in:Leukemia 2016-03, Vol.30 (3), p.594-604
Main Authors: Ma, J, Nie, K, Redmond, D, Liu, Y, Elemento, O, Knowles, D M, Tam, W
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Base Sequence
Binding Sites
Carcinogenesis - genetics
Carcinogenesis - metabolism
Carcinogenesis - pathology
Cell Cycle Checkpoints
Cell Line, Tumor
Development and progression
Epstein-Barr virus
Epstein-Barr Virus Infections - genetics
Epstein-Barr Virus Infections - metabolism
Epstein-Barr Virus Infections - pathology
Gene expression
Gene Expression Regulation, Neoplastic
Genetic aspects
Health aspects
Herpesvirus 4, Human - genetics
Herpesvirus 4, Human - pathogenicity
Host-Pathogen Interactions
Humans
Lymphoma, Large B-Cell, Diffuse - genetics
Lymphoma, Large B-Cell, Diffuse - metabolism
Lymphoma, Large B-Cell, Diffuse - pathology
Lymphomas
MicroRNA
MicroRNAs - genetics
MicroRNAs - metabolism
Molecular Sequence Data
Original
Paraffin Embedding
Positive Regulatory Domain I-Binding Factor 1
Protein Isoforms - antagonists & inhibitors
Protein Isoforms - genetics
Protein Isoforms - metabolism
Repressor Proteins - genetics
Repressor Proteins - metabolism
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
RNA, Small Nucleolar - genetics
RNA, Small Nucleolar - metabolism
Signal Transduction
Tissue Fixation
Viral Proteins - antagonists & inhibitors
Viral Proteins - genetics
Viral Proteins - metabolism
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Summary: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.
ISSN:0887-6924
1476-5551
DOI:10.1038/leu.2015.285