title: Epstein-Barr virus BART9 miRNA modulates LMP1 levels and affects growth rate of nasal NK T cell lymphomas.
abstract: Nasal NK/T cell lymphomas (NKTCL) are a subset of aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin's lymphomas. The role of EBV in pathogenesis of NKTCL is not clear. Intriguingly, EBV encodes more than 40 microRNAs (miRNA) that are differentially expressed and largely conserved in lymphocryptoviruses. While miRNAs play a critical role in the pathogenesis of cancer, especially lymphomas, the expression and function of EBV transcribed miRNAs in NKTCL are not known. To examine the role of EBV miRNAs in NKTCL, we used microarray profiling and qRT-PCR to identify and validate expression of viral miRNAs in SNK6 and SNT16 cells, which are two independently derived NKTCL cell lines that maintain the type II EBV latency program. All EBV BART miRNAs except BHRF-derived miRNAs were expressed and some of these miRNAs are expressed at higher levels than in nasopharyngeal carcinomas. Modulating the expression of BART9 with antisense RNAs consistently reduced SNK6 and SNT16 proliferation, while antisense RNAs to BARTs-7 and -17-5p affected proliferation only in SNK6 cells. Furthermore, the EBV LMP-1 oncoprotein and transcript levels were repressed when an inhibitor of BART9 miRNA was transfected into SNK6 cells, and overexpression of BART9 miRNA increased LMP-1 protein and mRNA expression. Our data indicate that BART9 is involved in NKTCL proliferation, and one of its mechanisms of action appears to be regulating LMP-1 levels. Our findings may have direct application for improving NKTCL diagnosis and for developing possible novel treatment approaches for this tumor, for which current chemotherapeutic drugs have limited effectiveness.
authors.affiliation: Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: Hart
authors.initials: H
authors.lastname: Donahue
authors.forename: David
authors.initials: D
authors.lastname: Garcia
authors.forename: Jie
authors.initials: J
authors.lastname: Tan
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Rice
authors.forename: Paul D
authors.initials: PD
authors.lastname: Ling
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002277:Carcinoma; D049109:Cell Proliferation; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000473:pathology* / Q000821:virology; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D007694:Killer Cells, Natural / Q000378:metabolism / Q000473:pathology*; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D035683:MicroRNAs / Q000235:genetics*; D009297:Nasal Mucosa / Q000378:metabolism / Q000473:pathology*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D014408:Biomarkers, Tumor; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D035683:MicroRNAs; D012333:RNA, Messenger; D012367:RNA, Viral; D014763:Viral Matrix Proteins; D014764:Viral Proteins
references.citation: J Virol. 2011 Jan;85(2):996-1010
references.pmid: 21068248
references.citation: J Exp Med. 2008 Oct 27;205(11):2551-60
references.pmid: 18838543
references.citation: Nature. 2008 Sep 4;455(7209):58-63
references.pmid: 18668040
references.citation: Clin Microbiol Infect. 2009 Nov;15(11):982-8
references.pmid: 19874382
references.citation: Bioinformatics. 2003 Jan 22;19(2):185-93
references.pmid: 12538238
references.citation: Nat Rev Cancer. 2006 Nov;6(11):857-66
references.pmid: 17060945
references.citation: RNA. 2006 May;12(5):733-50
references.pmid: 16540699
references.citation: Front Biosci. 2006 Sep 01;11:2672-713
references.pmid: 16720343
references.citation: Mol Cell Biol. 2008 Apr;28(7):2167-74
references.pmid: 18212054
references.citation: J Immunol. 2009 Feb 15;182(4):1919-28
references.pmid: 19201845
references.citation: J Virol. 2006 Aug;80(15):7382-93
references.pmid: 16840319
references.citation: Nat Methods. 2005 Apr;2(4):269-76
references.pmid: 15782219
references.citation: Oncogene. 2000 Mar 9;19(11):1400-10
references.pmid: 10723131
references.citation: Nature. 2009 Jan 22;457(7228):421-5
references.pmid: 19158788
references.citation: Mol Immunol. 2005 Mar;42(5):627-41
references.pmid: 15607822
references.citation: Br J Haematol. 2003 Jun;121(5):805-14
references.pmid: 12780797
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16164-9
references.pmid: 17911266
references.citation: J Biol Chem. 2007 Aug 10;282(32):23716-24
references.pmid: 17569667
references.citation: PLoS Pathog. 2006 Mar;2(3):e23
references.pmid: 16557291
references.citation: J Virol. 2008 Nov;82(21):10436-43
references.pmid: 18753206
references.citation: Nat Rev Cancer. 2006 Apr;6(4):259-69
references.pmid: 16557279
references.citation: Virology. 2009 Apr 10;386(2):387-97
references.pmid: 19217135
references.citation: PLoS One. 2010 Sep 20;5(9):
references.pmid: 20862214
references.citation: J Leukoc Biol. 2009 Dec;86(6):1345-50
references.pmid: 19741158
references.citation: J Virol. 2010 Mar;84(6):2787-97
references.pmid: 20053736
references.citation: Int J Cancer. 1996 Nov 4;68(3):285-90
references.pmid: 8903467
references.citation: Virology. 2008 Dec 20;382(2):257-66
references.pmid: 18950829
references.citation: Nat Rev Cancer. 2004 Oct;4(10):757-68
references.pmid: 15510157
references.citation: J Virol. 2007 Jan;81(2):1033-6
references.pmid: 17079300
references.citation: Virology. 2006 Jul 5;350(2):381-93
references.pmid: 16533516
references.citation: Oncogene. 1996 Nov 21;13(10):2243-54
references.pmid: 8950992
references.citation: Nucleic Acids Res. 2008 Feb;36(2):666-75
references.pmid: 18073197
references.citation: Nucleic Acids Res. 2005 Nov 27;33(20):e179
references.pmid: 16314309
references.citation: J Allergy Clin Immunol. 2005 Aug;116(2):251-61; quiz 262
references.pmid: 16083776
references.citation: Cell Cycle. 2008 Oct;7(20):3143-8
references.pmid: 18843198
references.citation: Blood. 1993 May 15;81(10):2688-95
references.pmid: 8387835
references.citation: J Virol. 2008 Jun;82(11):5295-306
references.pmid: 18367535
references.citation: Leuk Lymphoma. 2009 Nov;50(11):1773-84
references.pmid: 19883307
references.citation: J Virol. 2008 Feb;82(4):1946-58
references.pmid: 18057241
references.citation: Hematol Oncol. 1990 Sep-Oct;8(5):271-81
references.pmid: 1979042
references.citation: Blood. 2001 Feb 1;97(3):708-13
references.pmid: 11157488
references.citation: Cancer Res. 2008 Mar 1;68(5):1436-42
references.pmid: 18316607
references.citation: Lancet. 1990 Jan 20;335(8682):128-30
references.pmid: 1967431
references.citation: Int J Hematol. 2008 Mar;87(2):110-117
references.pmid: 18256789
references.citation: Blood. 2009 Oct 8;114(15):3265-75
references.pmid: 19641183
references.citation: J Virol. 2009 Mar;83(5):2357-67
references.pmid: 19091858
references.citation: Nucleic Acids Res. 2011 Mar;39(5):1880-93
references.pmid: 21062812
references.citation: Curr Opin Hematol. 2008 Jul;15(4):352-8
references.pmid: 18536574
references.citation: J Virol. 1990 Apr;64(4):1667-74
references.pmid: 2157049