MicroRNA-146a Downregulates NFκB Activity via Targeting TRAF6 and Functions as a Tumor Suppressor Having Strong Prognostic Implications in NK/T Cell Lymphoma
MicroRNA-146a Downregulates NFκB Activity via Targeting TRAF6 and Functions as a Tumor Suppressor Having Strong Prognostic Implications in NK/T Cell Lymphoma
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DOI：
10.1158/1078-0432.ccr-11-0494
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发表时间：
2011-07-15
影响因子：
11.5
通讯作者：
Kim, Chul-Woo
中科院分区：
文献类型：
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作者：
Paik, Jin Ho;Jang, Ji-Young;Kim, Chul-Woo
目的：我们研究了 microRNA 在结外 NK/T 细胞淋巴瘤 (NKTL) 中的预后意义。实验设计：我们使用实时 PCR 测量了 NKTL 组织和细胞系中的 miRNA 表达，并使用细胞系分析了其在 NKTL 中的作用。结果：多变量分析显示 miR-146a 表达低（P < 0.001；HR = 13.110），原发性非上呼吸消化道病变（非 UAT；P = 0.008；HR = 5.376）和高国际预后指数（IPI；>= 3；P = 0.013；HR = 3.584）是独立的不良预后因素。 miR-146a 表达可将 UAT-NKTL 细分为 2 个预后组，从而产生以下预后组：(i) UAT(Low-146a)、(ii) UAT(High-146a) 和 (iii) 非 UAT。与UAT(High-146a)相比，UAT(Low-146a)的预后明显较差(P < 0.001；HR = 15.620)，与非UAT组相似。在体外，miR-146a 在 NKTL 细胞系 SNK6 和 YT 中过表达，抑制核因子 kappa B (NF kappa B) 活性，抑制细胞增殖，诱导细胞凋亡并增强化疗敏感性。 TNF 受体相关因子 6（miR-146a 的靶标和已知的 NF kappa B 激活剂）在 SNK6 和 YT 细胞中被 miR-146a 下调。在 SNK6 和 YT 细胞以及 miR-146a 低表达的 NKTL 组织中观察到 miR-146a 基因的启动子甲基化，并且通过在 SNK6 和 YT 细胞中用去甲基化剂转换甲基化状态来诱导 miR-146a 表达。结论：这些结果表明 miR-146a 可能在 NKTL 中发挥有效的肿瘤抑制作用，并可用于患者评估和治疗靶向。临床癌症研究； 17(14); 4761-71. (C)2011 AACR。
Purpose: We investigated prognostic implications of microRNAs in extranodal NK/T cell lymphoma (NKTL).Experimental Design: We measured miRNA expression in NKTL tissues and cell lines, using real-time PCR, and analyzed its role in NKTL, using cell lines.Results: Multivariate analysis showed low miR-146a expression (P < 0.001; HR = 13.110), primary non-upper aerodigestive tract lesion (non-UAT; P = 0.008; HR = 5.376) and high International Prognostic Index (IPI; >= 3; P = 0.013; HR = 3.584) to be independent poor prognostic factors. miR-146a expression could subdivide UAT-NKTL into 2 prognostic groups, resulting in the following prognostic groups: (i) UAT(Low-146a), (ii) UAT(High-146a), and (iii) non-UAT. Compared with UAT(High-146a), UAT(Low-146a) showed distinctively poor prognosis (P < 0.001; HR = 15.620), similar to the non-UAT group. In vitro, miR-146a overexpression in NKTL cell lines, SNK6 and YT, inhibited nuclear factor kappa B (NF kappa B) activity, suppressed cell proliferation, induced apoptosis, and enhanced chemosensitivity. TNF receptor-associated factor 6, a target of miR-146a and a known NF kappa B activator, was downregulated by miR-146a in SNK6 and YT cells. Promoter methylation of miR-146a gene was observed in SNK6 and YT cells, as well as in NKTL tissues with low miR-146a expression, and miR-146a expression was induced by the conversion of methylation status with a demethylating agent in SNK6 and YT cells.Conclusions: These results suggest that miR-146a might function as a potent tumor suppressor in NKTL and be useful for patient assessment and therapeutic targeting. Clin Cancer Res; 17(14); 4761-71. (C)2011 AACR.