MicroRNA profiling of Epstein-Barr virus-associated NK/T-cell lymphomas by deep sequencing

PLoS One. 2012;7(8):e42193. doi: 10.1371/journal.pone.0042193. Epub 2012 Aug 3.

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / metabolism*
  • Epstein-Barr Virus Infections / pathology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Herpesvirus 4, Human*
  • Humans
  • Interleukin-1alpha / biosynthesis
  • Interleukin-1alpha / genetics
  • Lymphoma, Extranodal NK-T-Cell / genetics
  • Lymphoma, Extranodal NK-T-Cell / metabolism*
  • Lymphoma, Extranodal NK-T-Cell / pathology
  • Lymphoma, Extranodal NK-T-Cell / virology
  • Male
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • RNA, Neoplasm / biosynthesis*
  • RNA, Neoplasm / genetics
  • Sequence Analysis, RNA

Substances

  • IL1A protein, human
  • Interleukin-1alpha
  • MIRN142 microRNA, human
  • MIRN205 microRNA, human
  • MicroRNAs
  • RNA, Neoplasm

Grants and funding

This research was supported by grant 107166 from the Deutsche Krebshilfe to G. Meister and F. Grässer; S. Barth was supported by the German Bundesministerium für Bildung und Forschung through grant NGFN-Plus #01GS0801/4 to F. Grässer. The contribution from the Meister lab was partially supported by the Max-Planck-Society, a grant from the German Bundesministerium für Bildung und Forschung through grant NGFN-Plus #01GS0801/5 (to G. Meister) and the Bavarian Ministry for Education and Science (BayGene to G. Meister). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.