Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that fine-tune the responses of the cell by modulating the cell transcriptome and gene expression. MicroRNA 155 (miR-155) is a conserved multifunctional miRNA involved in multiple roles including the modulation of the immune responses. When deregulated, miR-155 can also contribute to cancer as has been demonstrated in several human malignancies such as diffuse large B cell lymphoma, chronic lymphocytic leukemia, as well as in Epstein–Barr virus (EBV)-induced B cell transformation. Avian oncogenic viruses such as Marek’s disease virus (MDV), avian leukosis virus (ALV), and reticuloendotheliosis virus (REV) that account for more than 90% of cancers in avian species, also make use of the miR-155 pathway during oncogenesis. While oncogenic retroviruses, such as ALV, activate miR-155 by insertional activation, acutely transforming retroviruses use transduced oncogenes such as v-rel to upregulate miR-155 expression. MDV on the other hand, encodes a functional miR-155 ortholog mdv1-miR-M4, similar to the miR-155 ortholog kshv-miR-K11 present in Kaposi’s sarcoma-associated herpesvirus (KSHV). We have shown that mdv1-miR-M4 is critical for the induction of MDV-induced lymphomas further demonstrating the oncogenic potential of miR-155 pathway in cancers irrespective of the diverse etiology. In this review, we discuss on our current understanding of miR-155 function in virus-induced lymphomas focusing primarily on avian oncogenic viruses.
Highlights
Epstein–Barr virus (EBV), another oncogenic herpesvirus associated with B-cell lymphomas, including Hodgkin’s lymphoma, diffuse large B cell lymphoma (DLBCL), and Burkitt’s lymphoma in humans, upregulates miR-155 resulting in escalated cell proliferation and neoplastic transformation [43,44]
Our study revealed that miR-M4 that accounted for more than two-thirds of the miRNA reads in tumor cells, is the single most important miRNA in this cluster that contributed to oncogenesis [47,51]
Using viruses modified by reverse genetics of the infectious BAC clone of the oncogenic RB-1B strain of Marek’s disease virus (MDV), we showed that the deletion of the six-miRNA cluster 1 from the viral genome abolished the oncogenicity of the virus [52,54], and the loss of oncogenicity appeared to be primarily due to miR-M4 in the cluster
Summary
Oncogenic viruses are associated with ~20% of cancers in humans, while in commercial livestock species such as poultry, they account for more than 90% of neoplastic diseases. MiRNA biogenesis pathway itself can be adversely affected in several cancers due to multiple causes These include aberrations in the genome, epigenetic modifications, virus-induced changes, metabolic imbalances, oxidative disequilibrium, dysregulation of oncogenes, and mutations in tumor suppressor genes. Such changes can lead to defective microprocessor proteins that can affect different steps in miRNA biogenesis from transcriptional initiation of pri-miRNA to the formation of functional mature miRNA. We highlight the significant role of miR-155 and its virus-encoded orthologs in neoplastic transformation by avian oncogenic viruses
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