title: MicroRNA-34a promotes genomic instability by a broad suppression of genome maintenance mechanisms downstream of the oncogene KSHV-vGPCR.
abstract: The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded chemokine receptor vGPCR acts as an oncogene in Kaposi's sarcomagenesis. Until now, the molecular mechanisms by which the vGPCR contributes to tumor development remain incompletely understood. Here, we show that the KSHV-vGPCR contributes to tumor progression through microRNA (miR)-34a-mediated induction of genomic instability. Large-scale analyses on the DNA, gene and protein level of cell lines derived from a mouse model of vGPCR-driven tumorigenesis revealed that a vGPCR-induced upregulation of miR-34a resulted in a broad suppression of genome maintenance genes. A knockdown of either the vGPCR or miR-34a largely restored the expression of these genes and confirmed miR-34a as a downstream effector of the KSHV-vGPCR that compromises genome maintenance mechanisms. This novel, protumorigenic role of miR-34a questions the use of miR-34a mimetics in cancer therapy as they could impair genome stability.
authors.affiliation: Molecular Tumor Genetics and Immunogenetics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.|Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Claudia J
authors.initials: CJ
authors.lastname: Krause
authors.affiliation: Mass Spectrometry Group, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Popp
authors.affiliation: Molecular Tumor Genetics and Immunogenetics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Nanthakumar
authors.initials: N
authors.lastname: Thirunarayanan
authors.affiliation: Mass Spectrometry Group, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Dittmar
authors.affiliation: Molecular Tumor Genetics and Immunogenetics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
authors.affiliation: Molecular Tumor Genetics and Immunogenetics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Müller
mesh_terms: D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D020869:Gene Expression Profiling; D042822:Genomic Instability / Q000235:genetics*; D019288:Herpesvirus 8, Human / Q000235:genetics*; D007553:Isotope Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics*; D012514:Sarcoma, Kaposi / Q000235:genetics*
chemical_list: C115448:G protein-coupled receptor, Human herpesvirus 8; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D019707:Receptors, Chemokine
keywords: KSHV; genome maintenance mechanisms; genomic instability; microRNA-34a; vGPCR