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The Epstein-Barr virus (EBV) is an oncogenic human Herpes virus involved in the pathogenesis of nasal NK/T-cell lymphoma. EBV encodes microRNAs (miRNAs) and induces changes in the host cellular miRNA profile. MiRNAs are short non- coding RNAs of about 19-25 nt length that regulate gene expression by post- transcriptional mechanisms and are frequently deregulated in human malignancies including cancer. The microRNA profiles of EBV-positive NK/T-cell lymphoma, non- infected T-cell lymphoma and normal thymus were established by deep sequencing of small RNA libraries. The comparison of the EBV-positive NK/T-cell vs. EBV- negative T-cell lymphoma revealed 15 up- und 16 down-regulated miRNAs. In contrast, the majority of miRNAs was repressed in the lymphomas compared to normal tissue. We also identified 10 novel miRNAs from known precursors and two so far unknown miRNAs. The sequencing results were confirmed for selected miRNAs by quantitative Real-Time PCR (qRT-PCR). We show that the proinflammatory cytokine interleukin 1 alpha (IL1A) is a target for miR-142-3p and the oncogenic BCL6 for miR-205. MiR-142-3p is down-regulated in the EBV-positive vs. EBV- negative lymphomas. MiR-205 was undetectable in EBV-negative lymphoma and strongly down-regulated in EBV-positive NK/T-cell lymphoma as compared to thymus. The targets were confirmed by reporter assays and by down-regulation of the proteins by ectopic expression of the cognate miRNAs. Taken together, our findings demonstrate the relevance of deregulated miRNAs for the post- transcriptional gene regulation in nasal NK/T-cell lymphomas. [ABSTRACT FROM AUTHOR]

Abstract: The Epstein–Barr virus (EBV) is an oncogenic Herpes virus involved in the induction of a variety of human tumours. It was the first virus found to encode microRNAs (miRNAs). MiRNAs are short, non-coding RNAs that in most cases negatively regulate gene expression at the post-transcriptional level. EBV-transformed cells express at least 44 mature viral miRNAs that target viral and cellular genes. In addition, EBV-infection severely deregulates the miRNA profile of the host cell. The presently available information indicates that the virus uses its miRNAs to inhibit the apoptotic response of the infected cell as a means to establish a latent infection. Likewise, EBV-encoded miRNAs interfere in the expression of viral genes in order to mask the infected cell from the immune response. Cellular targets of viral miRNAs are involved in protein traffic within the cell and regulate innate immunity. MiRNA profiling of diffuse large B-cell lymphoma (DLBCL) and nasal NK/T-cell lymphoma (NKTL) showed that only 2% of the miRNAs are derived from the virus, while viral miRNAs comprise up to 20% of the total miRNA in nasopharyngeal carcinoma (NPC) and probably contribute to the formation or maintenance of NPC. The presence of viral miRNAs in exosomes raises the fascinating possibility that virus-infected cells regulate gene expression in the surrounding tissue to avert destruction by the immune system. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation. [Copyright &y& Elsevier]

Abstract: The Epstein–Barr virus (EBV) growth-transforms B-lymphocytes. The virus-encoded nuclear antigen 2 (EBNA2) is essential for transformation and activates gene expression by association with DNA-bound transcription factors such as RBPJκ (CSL/CBF1). We have previously shown that EBNA2 contains symmetrically dimethylated Arginine (sDMA) residues. Deletion of the RG-repeat results in a reduced ability of the virus to immortalise B-cells. We now show that the RG repeat also contains asymmetrically dimethylated Arginines (aDMA) but neither non-methylated (NMA) Arginines nor citrulline residues. We demonstrate that only aDMA-containing EBNA2 is found in a complex with DNA-bound RBPJκ in vitro and preferentially associates with the EBNA2-responsive EBV C, LMP1 and LMP2A promoters in vivo. Inhibition of methylation in EBV-infected cells results in reduced expression of the EBNA2-regulated viral gene LMP1, providing additional evidence that methylation is a prerequisite for DNA-binding by EBNA2 via association with the transcription factor RBPJκ. [Copyright &y& Elsevier]