EBV-encoded miR-BART20-5p and miR-BART8 inhibit the IFN-γ-STAT1 pathway associated with disease progression in nasal NK-cell lymphoma
Journal
American Journal of Pathology
Journal Volume
184
Journal Issue
4
Pages
1185-1197
Date Issued
2014
Author(s)
Huang W.-T.
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-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.
SDGs
Other Subjects
doxorubicin; gamma interferon; luciferase; microRNA; microrna bart20 5p; microrna bart8; microrna let7a; protein p53; Renilla luciferin 2 monooxygenase; STAT1 protein; unclassified drug; gamma interferon; microRNA; STAT1 protein; STAT1 protein, human; transcriptome; 3' untranslated region; article; binding site; cancer prognosis; cancer resistance; cancer survival; chromatin immunoprecipitation; controlled study; enzyme linked immunosorbent assay; Epstein Barr virus; Epstein Barr virus infection; flow cytometry; gene overexpression; human; human cell; leukemia cell; leukemia cell line; NK T cell lymphoma; overall survival; priority journal; promoter region; quantitative analysis; real time polymerase chain reaction; signal transduction; transcription regulation; tumor growth; tumor suppressor gene; virus replication; Western blotting; wild type; complication; disease course; DNA microarray; genetics; immunology; lymphoma; natural killer cell; nose tumor; pathology; reverse transcription polymerase chain reaction; tumor cell line; virology; Blotting, Western; Cell Line, Tumor; Chromatin Immunoprecipitation; Disease Progression; Enzyme-Linked Immunosorbent Assay; Epstein-Barr Virus Infections; Flow Cytometry; Herpesvirus 4, Human; Humans; Interferon-gamma; Killer Cells, Natural; Lymphoma; MicroRNAs; Nose Neoplasms; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT1 Transcription Factor; Transcriptome
Publisher
Elsevier Inc.
Type
journal article