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.
Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.