Abstract
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.
Highlights
The Epstein-Barr Virus (EBV) is an oncogenic human Herpes virus that is involved in the pathogenesis of nasopharyngeal carcinoma (NPC), stomach carcinoma and various tumours of Band T-cell origin such as Burkitt’s and Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL) and nasal NK/T-cell lymphoma
Its oncogenic property is highlighted by the ability of EBV to growth-transform Blymphocytes; these so-called lymphoblastoid cell lines (LCL’s) are the in vitro correlate of B-cell lymphoproliferative disorders that often arise under immunosuppression
In the thymus small RNA library, 69% of the 46340 reads were identified as miRNA sequences, the small RNA library from EBV-negative lymphoma yielded 86% miRNA sequences from 35437 reads while EBV-positive NK/T-cell lymphoma library showed a reduced amount of 53% of miRNA-derived sequences among 81889 reads
Summary
The Epstein-Barr Virus (EBV) is an oncogenic human Herpes virus that is involved in the pathogenesis of nasopharyngeal carcinoma (NPC), stomach carcinoma and various tumours of Band T-cell origin such as Burkitt’s and Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL) and nasal NK/T-cell lymphoma (for review, see [1]). In the various EBVassociated tumour entities, the virus expresses different sets of transformation-associated proteins as well as non-coding RNAs [2]. These include the so-called EBER-RNAs, a snoRNA [3] and a set of 25 miRNAs [4,5,6]. Association with a target mRNA results in either translational repression or mRNA degradation leading to reduced protein synthesis (for review, see [9]). Among the EBV-associated tumours, NPC and nasal NK/T-cell lymphoma are the two entities that are virtually always infected with EBV. NK/T-cell lymphomas are mainly found in South-east Asia where they constitute about 3–9%
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