Reactive nitrogen species-dependent DNA damage in EBV-associated nasopharyngeal carcinoma: The relation to STAT3 activation and EGFR expression
Reactive nitrogen species-dependent DNA damage in EBV-associated nasopharyngeal carcinoma: The relation to STAT3 activation and EGFR expression
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DOI：
10.1002/ijc.23415
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发表时间：
2008-06-01
影响因子：
6.4
通讯作者：
Kawanishi, Shosuke
中科院分区：
文献类型：
--
作者：
Ma, Ning;Kawanishi, Michiko;Kawanishi, Shosuke
鼻咽癌（NPC）与EB病毒（EBV）感染密切相关。最近，活性氮和氧被认为是通过DNA损伤参与炎症相关的致癌作用。本研究采用免疫荧光双染法检测了中国南方鼻咽癌患者鼻咽活检和手术标本中8-硝基鸟嘌呤（DNA硝化损伤）和8-氧代-7，8-二氢-2 '-脱氧胍基核苷（DNA氧化损伤）的形成。鼻咽癌患者间质中的癌细胞和炎性细胞均可见较强的DNA损伤。在8-硝基鸟嘌呤阳性癌细胞的胞浆中检测到强烈的iNOS免疫反应。在慢性鼻咽炎EBV阳性患者的上皮细胞中也观察到DNA损伤和iNOS表达，尽管其强度明显弱于NPC患者。在EBV阴性的受试者中，没有或很少的DNA损伤和iNOS表达。EGFR和磷酸化STAT 3在NPC患者癌细胞中强表达，而NF-κ B B不表达，提示STAT 3依赖性机制在NPC癌变过程中具有重要意义。IL-6主要表达于EB病毒感染者鼻咽组织的炎性细胞。在所有EBV感染患者的癌细胞中检测到EBV编码的RNA（EBER）和潜伏膜蛋白1（LMP 1）。在体外细胞系统中，在表达LMP 1的细胞中观察到EGFR的核积聚，并且IL-6诱导磷酸化STAT 3和iNOS。这些数据表明，EGFR的核积累和IL-6激活STAT 3在iNOS表达和由此产生的DNA损伤中起关键作用，导致EBV介导的NPC。(C)2008威利利斯公司
Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. Recently, reactive nitrogen and oxygen species are considered to participate in inflammation-related carcinogenesis through DNA damage. In our study, we obtained biopsy and surgical specimens of nasopharyngeal tissues from NPC patients in southern China, and performed double immunofluorescent staining to examine the formation of 8-nitroguanine, a nitrative DNA lesion and 8-oxo-7,8-dihydro-2'-deoxygua-nosine, an oxidative DNA lesion, in these specimens. Strong DNA lesions were observed in cancer cells and inflammatory cells in stroma of NPC patients. Intensive immunoreactivity of iNOS was detected in the cytoplasm of 8-nitroguanine-positive cancer cells. DNA lesions and iNOS expression were also observed in epithelial cells of EBV-positive patients with chronic nasopharyngitis, although their intensities were significantly weaker than those in NPC patients. In EBV-negative subjects, no or little DNA lesions and iNOS expression were observed. EGFR and phosphorylated STAT3 were strongly expressed in cancer cells of NPC patients, but NF-kappa B was not expressed, suggesting that STAT3-dependent mechanism is important for NPC carcinogenesis. IL-6 was expressed mainly in inflammatory cells of nasopharyngeal tissues of EBV-infected patients. EBV-encoded RNAs (EBERs) and latent membrane protein 1 (LMP1) were detected in cancer cells from all EBV-infected patients. In vitro cell system, nuclear accumulation of EGFR was observed in LMP1-expressing cells, and IL-6 induced phosphorylated STAT3 and iNOS. These data suggest that nuclear accumulation of EGFR and STAT3 activation by IL-6 play the key role in iNOS expression and resultant DNA damage, leading to EBV-mediated NPC. (C) 2008 Wiley-Liss, Inc.