title: The Epstein Barr-encoded BART-6-3p microRNA affects regulation of cell growth and immuno response in Burkitt lymphoma.
abstract: BACKGROUND
  Burkitt lymphoma is an aggressive B-cell lymphoma presenting in three clinical forms: endemic, sporadic and immunodeficiency-associated. More than 90% of endemic Burkitt lymphoma carry latent Epstein-Barr virus, whereas only 20% of sporadic Burkitt lymphoma are associated with Epstein-Barr infection. Although the Epstein-Barr virus is highly related with the endemic form, how and whether the virus participates in its pathogenesis remains to be fully elucidated. In particular, the virus may impair cellular gene expression by its own encoded microRNAs.
  
  
  METHODS
  Using microRNA profiling we compared Epstein-Barr-positive and Epstein-Barr-negative Burkitt lymphoma cases for both cellular and viral microRNAs. The array results were validated by qRT-PCR, and potential targets of viral microRNAs were then searched by bioinformatic predictions, and classified in functional categories, according to the Gene Ontology. Our findings were validated by in vitro functional studies and by immunohistochemistry on a larger series of cases.
  
  
  RESULTS
  We showed that a few cellular microRNAs are differentially expressed between Epstein-Barr-positive and Epstein-Barr-negative Burkitt lymphoma cases, and identified a subset of viral microRNAs expressed in Epstein-Barr-positive Burkitt lymphomas. Of these, we characterized the effects of viral BART6-3p on regulation of cellular genes. In particular, we analyzed the IL-6 receptor genes (IL-6Rα and IL-6ST), PTEN and WT1 expression for their possible relevance to Burkitt lymphoma. By means of immunohistochemistry, we observed a down-regulation of the IL-6 receptor and PTEN specifically in Epstein-Barr-positive Burkitt lymphoma cases, which may result in the impairment of key cellular pathways and may contribute to malignant transformation. On the contrary, no differences were observed between Epstein-Barr-positive and Epstein-Barr-negative Burkitt lymphoma cases for WT1 expression.
  
  
  CONCLUSIONS
  Our preliminary results point at an active role for the Epstein-Barr virus in Burkitt lymphomagenesis and suggest new possible mechanisms used by the virus in determining dysregulation of the host cell physiology.
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via delle Scotte, 6-53100 Siena, Italy.
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Ambrosio
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via delle Scotte, 6-53100 Siena, Italy.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Navari
authors.affiliation: Department of Pathology, Hospital Universitario Marques de Valdecilla, IFIMAV, Santander, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Di Lisio
authors.affiliation: Bioinformatics Unit (UBio), Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Eduardo Andres
authors.initials: EA
authors.lastname: Leon
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via delle Scotte, 6-53100 Siena, Italy.|Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Onnis
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via delle Scotte, 6-53100 Siena, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gazaneo
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via delle Scotte, 6-53100 Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mundo
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ulivieri
authors.affiliation: Department of Pathology, Hospital Universitario Marques de Valdecilla, IFIMAV, Santander, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gomez
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via delle Scotte, 6-53100 Siena, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Lazzi
authors.affiliation: Department of Pathology, Hospital Universitario Marques de Valdecilla, IFIMAV, Santander, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via delle Scotte, 6-53100 Siena, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Leoncini
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via delle Scotte, 6-53100 Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: De Falco
keywords: Burkitt lymphoma; EBV; MicroRNAs
references.citation: J Virol. 2011 Jan;85(2):996-1010
references.pmid: 21068248
references.citation: Cell Cycle. 2008 Nov 15;7(22):3595-600
references.pmid: 19001862
references.citation: Leuk Lymphoma. 2013 Oct;54(10):2190-9
references.pmid: 23402267
references.citation: PLoS Pathog. 2011 Aug;7(8):e1002193
references.pmid: 21901094
references.citation: Virology. 2009 Apr 10;386(2):387-97
references.pmid: 19217135
references.citation: RNA. 2006 Feb;12(2):192-7
references.pmid: 16373484
references.citation: N Engl J Med. 2006 Jun 8;354(23):2431-42
references.pmid: 16760443
references.citation: PLoS One. 2013;8(2):e56741
references.pmid: 23418597
references.citation: J Mol Diagn. 2004 Nov;6(4):378-85
references.pmid: 15507678
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: RNA. 2003 Mar;9(3):277-9
references.pmid: 12592000
references.citation: Nat Genet. 2001 May;28(1):21-8
references.pmid: 11326270
references.citation: Am J Rhinol Allergy. 2009 Jan-Feb;23(1):28-32
references.pmid: 19379608
references.citation: J Pathol. 2013 Nov;231(3):311-22
references.pmid: 23868181
references.citation: Proc Natl Acad Sci U S A. 1982 Dec;79(24):7824-7
references.pmid: 6961453
references.citation: PLoS Pathog. 2006 Mar;2(3):e23
references.pmid: 16557291
references.citation: Br J Surg. 1958 Nov;46(197):218-23
references.pmid: 13628987
references.citation: Leukemia. 2011 Dec;25(12):1869-1876
references.pmid: 21701491
references.citation: Nat Genet. 2012 Dec;44(12):1321-5
references.pmid: 23143597
references.citation: Semin Diagn Pathol. 2011 May;28(2):178-87
references.pmid: 21842703
references.citation: Am J Transplant. 2013 May;13(5):1305-16
references.pmid: 23489474
references.citation: J Exp Med. 1996 Apr 1;183(4):1399-406
references.pmid: 8666898
references.citation: Lancet. 1964 Feb 1;1(7327):252-3
references.pmid: 14090852
references.citation: Int J Cancer. 2009 Apr 15;124(8):1745-55
references.pmid: 19165855
references.citation: BMC Biotechnol. 2008 Sep 11;8:69
references.pmid: 18783629
references.citation: J Pathol. 2011 Jul;224(3):355-66
references.pmid: 21506127
references.citation: Annu Rev Immunol. 2005;23:1-21
references.pmid: 15771564
references.citation: PLoS One. 2010 Sep 24;5(9):
references.pmid: 20930934
references.citation: Blood. 2011 Mar 31;117(13):3596-608
references.pmid: 21245480
references.citation: J Pathol. 2012 Aug;227(4):392-403
references.pmid: 22431062
references.citation: N Engl J Med. 2006 Jun 8;354(23):2419-30
references.pmid: 16760442
references.citation: Science. 2013 Jul 26;341(6144):399-402
references.pmid: 23744781
references.citation: J Pathol. 2013 Oct;231(2):158-67
references.pmid: 23878065
references.citation: PLoS Pathog. 2012;8(5):e1002704
references.pmid: 22615564
references.citation: Proc Natl Acad Sci U S A. 1982 Dec;79(24):7837-41
references.pmid: 6818551
references.citation: J Virol Methods. 2012 Sep;184(1-2):46-54
references.pmid: 22609801
references.citation: J Comput Biol. 2001;8(5):549-56
references.pmid: 11694182
references.citation: Blood Cancer J. 2012 Aug 31;2:e84
references.pmid: 22941339
references.citation: Clin Microbiol Infect. 2009 Nov;15(11):982-8
references.pmid: 19874382
references.citation: Semin Cancer Biol. 2009 Dec;19(6):401-6
references.pmid: 19619656
references.citation: Br J Haematol. 2012 Mar;156(6):744-56
references.pmid: 22260300
references.citation: J Pathol. 2011 Mar;223(4):496-510
references.pmid: 21294123
references.citation: PLoS One. 2012;7(8):e44315
references.pmid: 22952953
references.citation: Int J Cancer. 2010 Mar 15;126(6):1316-26
references.pmid: 19530237
references.citation: PLoS One. 2011;6(11):e27271
references.pmid: 22102884
references.citation: Am Soc Clin Oncol Educ Book. 2013;:
references.pmid: 23714559