title: Modulation of MicroRNA Cluster miR-183-96-182 Expression by Epstein-Barr Virus Latent Membrane Protein 1.
abstract: Epstein-Barr virus (EBV) is an oncogenic human herpesvirus involved in the pathogenesis of Burkitt's lymphoma (BL) and various other lymphoproliferative disorders. In BL, EBV protein expression is restricted to EBV nuclear antigen 1 (EBNA1), but small noncoding RNAs such as EBV-encoded small RNAs (EBERs) and microRNAs (miRNAs) can also be detected. miRNAs play major roles in crucial processes such as proliferation, differentiation, and cell death. It has recently become clear that alterations in the expression profile of miRNAs contribute to the pathogenesis of a number of malignancies. During latent infection, EBV expresses 25 viral pre-miRNAs and modulates the expression of specific cellular miRNAs, such as miR-155 and miR-146, which potentially play a role in oncogenesis. Here, we established the small-RNA expression profiles of three BL cell lines. Using large-scale sequencing coupled to Northern blotting and real-time reverse transcription-PCR (RT-PCR) analysis validation, we demonstrated the differential expression of some cellular and viral miRNAs. High-level expression of the miR-183-96-182 cluster and EBV miR-BamHI A rightward transcript (miR-BART) cluster was significantly associated with EBV type I latency. This expression was not affected by viral reactivation since transforming growth factor β1 (TGF-β1) stimulation did not significantly change the miRNA profiles. However, using several approaches, including de novo infection with a mutant virus, we present evidence that the expression of latent membrane protein 1 (LMP-1) triggered downregulation of the expression of the miR-183-96-182 cluster. We further show that this effect involves the Akt signaling pathway.
  
  
  OBJECTIVE
  In addition to expressing their own miRNAs, herpesviruses also impact the expression levels of cellular miRNAs. This regulation can be either positive or negative and usually results in the perturbation of pathways to create a cellular environment that is more "virus-friendly." For example, EBV induces the expression of miR-155, a well-characterized oncomiR, which leads to increased cell proliferation and decreased cell death. Here, we show that EBV-encoded LMP-1 is also involved in the downregulation of a cluster of three miRNAs, miR-183, -96, and -182, which are known to be also repressed in several cancers. We therefore identify yet another potential player in EBV-induced oncogenesis.
authors.affiliation: UMR 1197 Inserm-Université Paris 11, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Lassad
authors.initials: L
authors.lastname: Oussaief
authors.affiliation: Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, Strasbourg, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Fendri
authors.affiliation: Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, Strasbourg, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Chane-Woon-Ming
authors.affiliation: German Cancer Research Center (DKFZ), mixed unit DKFZ/Inserm F100-U1074, Pathogenesis of Virus-Associated Tumors, Heidelberg, Germany.
authors.forename: Remy
authors.initials: R
authors.lastname: Poirey
authors.affiliation: German Cancer Research Center (DKFZ), mixed unit DKFZ/Inserm F100-U1074, Pathogenesis of Virus-Associated Tumors, Heidelberg, Germany.
authors.forename: Henri-Jacques
authors.initials: HJ
authors.lastname: Delecluse
authors.affiliation: UMR 1197 Inserm-Université Paris 11, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Joab
authors.affiliation: Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, Strasbourg, France spfeffer@unistra.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pfeffer
mesh_terms: D001483:Base Sequence; D015152:Blotting, Northern; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D055786:Gene Knockout Techniques; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D014763:Viral Matrix Proteins / Q000235:genetics*
chemical_list: D017931:DNA Primers; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C533449:MIRN183 microRNA, human; C541492:MIRN96 microRNA, human; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D014763:Viral Matrix Proteins