EBV-Encoded miR-BART20-5p and miR-BART8 Inhibit the IFN-γ–STAT1 Pathway Associated with Disease Progression in Nasal NK-Cell Lymphoma
摘要：
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-γweak/STAT1strong YT leukemic cells and IFN-γstrong/STAT1weak 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.
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关键词：
Humans Herpesvirus 4, Human Epstein-Barr Virus Infections Lymphoma Nose Neoplasms Disease Progression MicroRNAs Oligonucleotide Array Sequence Analysis Chromatin Immunoprecipitation Reverse Transcriptase Polymerase Chain Reaction
DOI：
10.1016/j.ajpath.2013.12.024
被引量：
年份：
2014
Elsevier
国家科技图书文献中心
(权威机构)
万方医学
dx.doi.org
Europe PMC
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