title: The Epstein-Barr virus (EBV)-induced tumor suppressor microRNA MiR-34a is growth promoting in EBV-infected B cells.
abstract: Epstein-Barr virus (EBV) infection of primary human B cells drives their indefinite proliferation into lymphoblastoid cell lines (LCLs). B cell immortalization depends on expression of viral latency genes, as well as the regulation of host genes. Given the important role of microRNAs (miRNAs) in regulating fundamental cellular processes, in this study, we assayed changes in host miRNA expression during primary B cell infection by EBV. We observed and validated dynamic changes in several miRNAs from early proliferation through immortalization; oncogenic miRNAs were induced, and tumor suppressor miRNAs were largely repressed. However, one miRNA described as a p53-targeted tumor suppressor, miR-34a, was strongly induced by EBV infection and expressed in many EBV and Kaposi's sarcoma-associated herpesvirus (KSHV)-infected lymphoma cell lines. EBV latent membrane protein 1 (LMP1) was sufficient to induce miR-34a requiring downstream NF-κB activation but independent of functional p53. Furthermore, overexpression of miR-34a was not toxic in several B lymphoma cell lines, and inhibition of miR-34a impaired the growth of EBV-transformed cells. This study identifies a progrowth role for a tumor-suppressive miRNA in oncogenic-virus-mediated transformation, highlighting the importance of studying miRNA function in different cellular contexts.
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for Virology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Forte
authors.forename: Raul E
authors.initials: RE
authors.lastname: Salinas
authors.forename: Christina
authors.initials: C
authors.lastname: Chang
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Linnstaedt
authors.forename: Eva
authors.initials: E
authors.lastname: Gottwein
authors.forename: Cassandra
authors.initials: C
authors.lastname: Jacobs
authors.forename: Dereje
authors.initials: D
authors.lastname: Jima
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dave
authors.forename: Micah A
authors.initials: MA
authors.lastname: Luftig
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D014763:Viral Matrix Proteins