Downregulation of miR-15a due to LMP1 promotes cell proliferation and predicts poor prognosis in nasal NK/T-cell lymphoma
Downregulation of miR-15a due to LMP1 promotes cell proliferation and predicts poor prognosis in nasal NK/T-cell lymphoma
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DOI：
10.1002/ajh.23570
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发表时间：
2014-01-01
影响因子：
12.8
通讯作者：
Harabuchi, Yasuaki
中科院分区：
文献类型：
--
作者：
Komabayashi, Yuki;Kishibe, Kan;Harabuchi, Yasuaki
鼻NK/ t细胞淋巴瘤（NNKTL）是一种与eb病毒（EBV）相关的恶性肿瘤，具有独特的临床和组织学特征。然而，其遗传特征迄今尚不清楚。MicroRNAs （miRNAs）通过调控基因表达在多种恶性肿瘤的发病机制中起着至关重要的作用。在本研究中，我们研究了特异性microrna是否与NNKTL的肿瘤行为有关。MiRNA阵列和定量RT-PCR分析显示，miR-15a在NNKTL细胞（SNK-1、SNK-6和SNT-8）中的表达水平远低于正常外周血NK细胞和ebv阴性NK细胞系KHYG-1。定量PCR和western blot分析显示，MYB和cyclin D1的表达在NNKTL细胞中较高，它们是miR-15a的有效靶点。转染miR-15a前体的NNKTL细胞（SNK-6和SNT-8）可降低MYB和cyclin D1水平，从而阻断G1/S转变和细胞增殖。敲低ebv编码的潜伏膜蛋白1 （LMP1）可显著增加SNK-6细胞中miR-15a的表达。在NNKTL组织中，我们发现与MYB和cyclin D1表达相关的miR-15a表达降低与NNKTL患者预后不良相关。这些数据表明，miR-15a的下调，可能是由LMP1引起的，通过MYB和cyclin D1诱导细胞增殖，参与了NNKTL的发病机制。因此，miR-15a可能是抗肿瘤治疗的潜在靶点和NNKTL的预后预测因子。点。中华血液学杂志，2014,29(4):444 - 444。(c) 2013 Wiley Periodicals, Inc.；
Nasal NK/T-cell lymphoma (NNKTL) is an Epstein-Barr virus (EBV)-associated malignancy and has distinct clinical and histological features. However, its genetic features are hitherto unclear. MicroRNAs (miRNAs) play a crucial role in the pathogenesis of several malignancies via regulating gene expression. In this study, we investigated whether the specific microRNAs were related to the tumor behaviors in NNKTL. MiRNA array and Quantitative RT-PCR analyses revealed that miR-15a was expressed at a much lower level in NNKTL cells (SNK-1, SNK-6, and SNT-8) than in normal peripheral NK cells and EBV-negative NK cell line KHYG-1. Quantitative PCR and western blot analyses showed that the expression of MYB and cyclin D1, which are validated targets of miR-15a, was higher in NNKTL cells. Transfection of NNKTL cells (SNK-6 and SNT-8) with a miR-15a precursor decreased MYB and cyclin D1 levels, thereby blocking G1/S transition and cell proliferation. Knockdown of EBV-encoded latent membrane protein 1 (LMP1) significantly increased miR-15a expression in SNK-6 cells. In NNKTL tissues, we found that reduced miR-15a expression, which correlated with MYB and cyclin D1 expression, was associated with poor prognosis of NNKTL patients. These data suggest that downregulation of miR-15a, possibly due to LMP1, implicates in the pathogenesis of NNKTL by inducing cell proliferation via MYB and cyclin D1. Thus, miR-15a could be a potential target for antitumor therapy and a prognostic predictor for NNKTL. Am. J. Hematol. 89:25-33, 2014. (c) 2013 Wiley Periodicals, Inc.