Critical role of the virus-encoded microRNA-155 ortholog in the induction of Marek's disease lymphomas

Autor: Lawrence Petherbridge, Hongtao Xu, Lydia Kgosana, Susan J. Baigent, Lorraine P. Smith, Yongxiu Yao, Yuguang Zhao, Venugopal Nair, James C. Green
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Lymphoma
viruses
Chick Embryo
Oncogenicity
medicine.disease_cause
Oncology/Hematological Malignancies
Virology/Effects of Virus Infection on Host Gene Expression
lcsh:QH301-705.5
Cells
Cultured
Genetics
0303 health sciences
Mutation
Vaccination
Genetics and Genomics/Gene Expression
Phenotype
3. Good health
Infectious Diseases
Virology/Animal Models of Infection
RNA
Viral
Research Article
lcsh:Immunologic diseases. Allergy
Molecular Sequence Data
Immunology
Genome
Viral
Biology
Microbiology
Virus
03 medical and health sciences
Virology
Marek Disease
medicine
Animals
Humans
Neoplastic transformation
Herpesvirus 2
Gallid
Molecular Biology
Gene
030304 developmental biology
Marek's disease
Base Sequence
030306 microbiology
Fibroblasts
biology.organism_classification
MicroRNAs
lcsh:Biology (General)
Parasitology
lcsh:RC581-607
Carcinogenesis
Chickens
Virology/Viruses and Cancer
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 7, Iss 2, p e1001305 (2011)
ISSN: 1553-7374
1553-7366
Popis: Notwithstanding the well-characterised roles of a number of oncogenes in neoplastic transformation, microRNAs (miRNAs) are increasingly implicated in several human cancers. Discovery of miRNAs in several oncogenic herpesviruses such as KSHV has further highlighted the potential of virus-encoded miRNAs to contribute to their oncogenic capabilities. Nevertheless, despite the identification of several possible cancer-related genes as their targets, the direct in vivo role of virus-encoded miRNAs in neoplastic diseases such as those induced by KSHV is difficult to demonstrate in the absence of suitable models. However, excellent natural disease models of rapid-onset Marek's disease (MD) lymphomas in chickens allow examination of the oncogenic potential of virus-encoded miRNAs. Using viruses modified by reverse genetics of the infectious BAC clone of the oncogenic RB-1B strain of MDV, we show that the deletion of the six-miRNA cluster 1 from the viral genome abolished the oncogenicity of the virus. This loss of oncogenicity appeared to be primarily due to the single miRNA within the cluster, miR-M4, the ortholog of cellular miR-155, since its deletion or a 2-nucleotide mutation within its seed region was sufficient to inhibit the induction of lymphomas. The definitive role of this miR-155 ortholog in oncogenicity was further confirmed by the rescue of oncogenic phenotype by revertant viruses that expressed either the miR-M4 or the cellular homolog gga-miR-155. This is the first demonstration of the direct in vivo role of a virus-encoded miRNA in inducing tumors in a natural infection model. Furthermore, the use of viruses deleted in miRNAs as effective vaccines against virulent MDV challenge, enables the prospects of generating genetically defined attenuated vaccines.
Author Summary MicroRNAs (miRNAs), encoded in the genomes of a number of organisms including several viruses, belong to a class of small RNA molecules that can function as key regulators of gene expression influencing various biological processes and diseases including cancer. Among all the miRNAs, miR-155 has been well documented for its direct role of oncogenesis in a number of species including chickens. Remarkably, miR-K12-11 and miR-M4, the miRNAs encoded by the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) and Marek's disease virus (MDV) respectively, have been shown to be functional orthologs of miR-155. There are no animal models of KSHV-induced tumors to examine the oncogenic potential of miR-K12-11. However, using recombinant mutant viruses in excellent models of MDV-induced lymphomas in their natural chicken hosts, we demonstrate that miR-M4 is critical for the induction of tumors. This is the first study that clearly demonstrates a direct role for a single miRNA in inducing cancer in an in vivo animal model. The ability of gga-miR-155 to rescue the oncogenic potential of miR-M4-deleted virus demonstrated the conservation of oncogenic functions the two miRNAs. Moreover, we show that virus attenuated by deleting the miRNAs can function as vaccines against virulent virus infection, enabling the prospects of generating novel molecularly-defined vaccines.
Databáze: OpenAIRE
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