TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas
TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas
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DOI：
10.1182/blood-2008-12-194852
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发表时间：
2009-09-17
期刊：
影响因子：
20.3
通讯作者：
Seto, Masao
中科院分区：
文献类型：
--
作者：
Honma, Keiichiro;Tsuzuki, Shinobu;Seto, Masao
核因子-κ B（NF-κ B）的组成性激活与淋巴恶性肿瘤的发生有关。我们先前已经表明，染色体6 q在眼边缘区B细胞淋巴瘤中经常缺失，并确定了TNFAIP 3/A20，NF-κ B途径的负调节因子，作为6 q缺失的主要靶点。在这里报道的研究中，我们将分析扩展到非霍奇金淋巴瘤的其他子集，发现A20在套细胞淋巴瘤和弥漫性大B细胞淋巴瘤中经常缺失。重要的是，这些淋巴瘤中也经常检测到A20启动子甲基化或基因突变，这增加了A20失活可能参与淋巴瘤发生的可能性。为了解决这个问题，我们进行了过表达实验，在淋巴瘤细胞系与A20缺失和下调表达的A20与EB病毒感染的淋巴母细胞系的siRNA技术。这些实验发现，A20的过表达诱导细胞凋亡，而A20的沉默与细胞凋亡抗性和增强的克隆形成相关。A20下调的细胞表现出增强的NF-κ B B活性，这可能是观察到的效果的原因。这些结果表明，我们的研究提供了一个新的见解，导致淋巴瘤的分子机制，特异性靶向NF-κ B途径可能是有利的治疗。（血。2009; 114：2467-2475）
The constitutive activation of nuclear factor-kappa B (NF-kappa B) has been implicated in tumorigenesis of lymphoid malignancies. We have previously shown that chromosome 6q was frequently deleted in ocular marginal zone B-cell lymphoma and identified TNFAIP3/A20, a negative regulator of NF-kappa B pathways, as the primary target for 6q deletion. In the study reported here, we extended the analysis to other subsets of non-Hodgkin lymphomas and found that A20 is frequently deleted in mantle cell lymphoma and diffuse large B-cell lymphoma. Importantly, A20 promoter methylation or gene mutation is also frequently detected in these lymphomas, raising the possibility that inactivation of A20 may be involved in lymphomagenesis. To address this question, we conducted overexpression experiments in lymphoma cell lines with A20 deletion and down-regulated expression of A20 with an siRNA technique in Epstein-Barr virus-infected lymphoblastoid cell lines. These experiments found that overexpression of A20 induced apoptosis and silencing of A20 was associated with resistance to apoptosis and enhanced clonogenicity. The cells with down-regulated A20 exhibited enhanced NF-kappa B activities, which may account for the observed effects. These results indicate that our study provides a novel insight into molecular mechanisms leading to lymphoma and that specific targeting of NF-kappa B pathways may be advantageous for treatment. (Blood. 2009; 114: 2467-2475)