title: EBV-encoded miR-BART20-5p and miR-BART8 inhibit the IFN-γ-STAT1 pathway associated with disease progression in nasal NK-cell lymphoma.
abstract: Nasal NK-cell lymphoma (NNL) is an Epstein-Barr virus (EBV)-associated lymphoma of cytotoxic natural killer (NK) cell origin. Because normal NK cells secrete the principal cytotoxic cytokine IFN-γ to suppress both tumor growth and viral replication, we investigated how EBV may have used miRNAs of viral origin to inhibit the IFN-γ-STAT1 pathway to facilitate viral replication and tumor growth. In EBV(-) Jurkat cells, transfection of miR-BART20-5p and miR-BART8 inhibited translation of luciferase-IFN-γ-3'-UTR and luciferase-STAT1-3'-UTR, respectively. In EBV(+) IFN-γ(weak)/STAT1(strong) YT leukemic cells and IFN-γ(strong)/STAT1(weak) NK92 cells, relative endogenous levels between miR-BART20-5p and IFN-γ mRNAs or between miR-BART8 and STAT1 mRNAs determined expression of the targets. Chromatin immunoprecipitation studies showed that STAT1 regulates the transcription of the tumor suppressor TP53 (encoding p53) and miR-let7a. Consistent with these findings, overexpression of miR-BART8 in YT cells or of miR-BART20-5p in NK92 cells inhibited p53 and increased resistance to doxorubicin. In 36 NNLs, the levels of miR-BART20-5p or miR-BART8 correlated inversely with the expression of STAT1. Additionally, in 46 NNLs, expression of both miR-BART20-5p and miR-BART8 identified a group of NNLs with decreased p53 mRNAs and evidence of disease progression. We conclude that miR-BART20-5p and miR-BART8 cause progression of nasal NK-cell lymphomas through inhibition of the IFN-γ-STAT1 pathway.
authors.affiliation: Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Huang
authors.affiliation: Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: chungwulin@yahoo.com.
authors.forename: Chung-Wu
authors.initials: CW
authors.lastname: Lin
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000473:pathology; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology / Q000821:virology; D035683:MicroRNAs / Q000276:immunology*; D009669:Nose Neoplasms / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D059467:Transcriptome
chemical_list: D035683:MicroRNAs; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma