Constitutive activation of distinct NF-κB signals in EBV-associated nasopharyngeal carcinoma
Constitutive activation of distinct NF-κB signals in EBV-associated nasopharyngeal carcinoma
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DOI：
10.1002/path.4239
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发表时间：
2013-11-01
影响因子：
7.3
通讯作者：
Lo, Kwok-Wai
中科院分区：
文献类型：
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作者：
Chung, Grace Tin-Yun;Lou, Wilson Pak-Kin;Lo, Kwok-Wai
非角化性鼻咽癌作为头颈癌的一种独特类型，与EBV感染和大量淋巴组织浸润密切相关。这种独特的组织学特征表明，局部炎症在鼻咽癌的发生发展中起着重要作用。我们全面描述了核因子-B信号，这是一个关键的炎症途径，可能有助于这种EBV相关癌症的发生。通过EMSA、Western blotting和免疫组织化学染色，在几乎所有EBV阳性的鼻咽癌中都发现了不同的NF-B复合体p50/p50/bcl3或p50/RelB的结构性激活。SiRNA或化学抑制核因子-B信号显著抑制EBV阳性鼻咽癌细胞C666-1的生长。基因表达谱鉴定了一些与细胞增殖、凋亡、免疫反应和转录有关的核因子-B靶基因。我们进一步证实，p50信号调节多种癌基因(MYB、BCL2)、趋化因子和趋化因子受体(CXCL9、CXCL10、CX3CL1和CCL20)的表达。这一发现支持了这些结构性激活的核因子-B信号在鼻咽癌发生和局部炎症中的关键作用。除了病毒癌蛋白LMP1的表达外，几种核因子-B调节因子(如TRAF3、TRAF2、NFKBIA、A20)的基因改变也是EB病毒相关性鼻咽癌中核因子-B异常激活的原因之一。除了表达LMP1的C15细胞外，所有鼻咽癌细胞系都至少存在其中一种基因改变。重要的是，TRAF3、TRAF2和A20的错义突变也在3/33(9.1%)的原发肿瘤中被检测到。连同报道的7.3%的原发鼻咽癌的LTbR扩增，至少16%的这种癌症患者发生了核因子-B通路的基因改变。这些发现表明，在EBV阳性的鼻咽癌细胞中，不同的NF-B信号被多种基因改变或EBV潜伏基因结构性地激活。版权所有(C)2013年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
As a distinct type of head and neck cancer, non-keratinizing nasopharyngeal carcinoma (NPC) is closely associated with EBV infection and massive lymphoid infiltration. The unique histological features suggest that local inflammation plays an important role in NPC tumourigenesis. We comprehensively characterized NF-B signalling, a key inflammatory pathway which might contribute to the tumourigenesis of this EBV-associated cancer. By EMSA, western blotting, and immunohistochemical staining, constitutive activation of distinct NF-B complexes, either p50/p50/Bcl3 or p50/RelB, was found in almost all EBV-positive NPC tumours. siRNA or chemical inhibition of NF-B signalling significantly inhibited the growth of EBV-positive NPC cells C666-1. Gene expression profiling identified a number of NF-B target genes involved in cell proliferation, apoptosis, immune response, and transcription. We further confirmed that p50 signals modulate the expression of multiple oncogenes (MYB, BCL2), chemokines, and chemokine receptors (CXCL9, CXCL10, CX3CL1, and CCL20). The findings support a crucial role of these constitutively activated NF-B signals in NPC tumourigenesis and local inflammation. In addition to expression of the viral oncoprotein LMP1, genetic alteration of several NF-B regulators (eg TRAF3, TRAF2, NFKBIA, A20) also contributes to the aberrant NF-B activation in EBV-associated NPC. Except for LMP1-expressing C15 cells, all NPC tumour lines harbour at least one of these genetic alterations. Importantly, missense mutations of TRAF3, TRAF2, and A20 were also detected in 3/33 (9.1%) primary tumours. Taken together with the reported LTBR amplification in 7.3% of primary NPCs, genetic alterations in NF-B pathways occurred in at least 16% of cases of this cancer. The findings indicate that distinct NF-B signals are constitutively activated in EBV-positive NPC cells by either multiple genetic changes or EBV latent genes. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.