Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
Am J Pathol. 2014 Apr;184(4):1185-97. doi: 10.1016/j.ajpath.2013.12.024.
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.
鼻 NK 细胞淋巴瘤（NNL）是一种与 EBV 相关的细胞毒性自然杀伤（NK）细胞来源的淋巴瘤。由于正常 NK 细胞分泌主要细胞毒性细胞因子 IFN-γ 来抑制肿瘤生长和病毒复制，我们研究了 EBV 如何利用源自病毒的 miRNA 来抑制 IFN-γ-STAT1 通路，从而促进病毒复制和肿瘤生长。在 EBV(-)Jurkat 细胞中，miR-BART20-5p 和 miR-BART8 的转染分别抑制了荧光素酶-IFN-γ-3'-UTR 和荧光素酶-STAT1-3'-UTR 的翻译。在 EBV(+)IFN-γ(弱)/STAT1(强)YT 白血病细胞和 IFN-γ(强)/STAT1(弱)NK92 细胞中，miR-BART20-5p 与 IFN-γ mRNAs 之间或 miR-BART8 与 STAT1 mRNAs 之间的相对内源性水平决定了靶基因的表达。染色质免疫沉淀研究表明 STAT1 调节肿瘤抑制因子 TP53（编码 p53）和 miR-let7a 的转录。与这些发现一致，在 YT 细胞中过表达 miR-BART8 或在 NK92 细胞中过表达 miR-BART20-5p 抑制了 p53 并增加了对阿霉素的耐药性。在 36 例 NNL 中，miR-BART20-5p 或 miR-BART8 的水平与 STAT1 的表达呈负相关。此外，在 46 例 NNL 中，miR-BART20-5p 和 miR-BART8 的表达鉴定出一组 NNL 中 p53 mRNAs 减少，并存在疾病进展的证据。我们得出结论，miR-BART20-5p 和 miR-BART8 通过抑制 IFN-γ-STAT1 通路导致鼻 NK 细胞淋巴瘤的进展。
