Zinc deficiency activates S100A8 inflammation in the absence of COX-2 and promotes murine oral-esophageal tumor progression.
Zinc deficiency activates S100A8 inflammation in the absence of COX-2 and promotes murine oral-esophageal tumor progression.
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DOI：
10.1002/ijc.25688
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发表时间：
2011-07-15
影响因子：
6.4
通讯作者：
Fong, Louise Y. Y.
中科院分区：
文献类型：
--
作者：
Wan, Shao-Gui;Taccioli, Cristian;Jiang, Yubao;Chen, Hongping;Smalley, Karl J.;Huang, Kun;Liu, Xiu-Ping;Farber, John L.;Croce, Carlo M.;Fong, Louise Y. Y.
关键词：
锌（Zn）缺乏（ZD）与人类口腔-食管癌的发病机制有关。以前，我们发现在ZD小鼠中，环氧合酶-2（考克斯-2）的基因缺失增强了N-亚硝基甲基苄胺诱导的前胃癌发生。相比之下，考克斯-2缺失在锌充足（ZS）小鼠中提供保护。我们假设ZD激活了对考克斯-2抑制不敏感的通路，从而促进了致癌作用。在模拟考克斯-2−/−药理学阻断考克斯-2−/−小鼠舌癌模型中，通过首先检查来自ZD与ZS饮食的考克斯-2−/−和野生型小鼠的前胃粘膜的转录组谱，然后研究所鉴定的标志物在小鼠前胃/舌前瘤形成和癌中的作用，来检验该假设。在暴露于舌致癌物4-硝基喹啉1-氧化物的考克斯-2−/−小鼠中，饮食ZD引发了被ZS预防的舌/食管/前胃癌。癌前ZD：考克斯-2−/−vs. ZS：考克斯-2−/−前胃具有炎症特征，促炎症基因S100 a8和S100 a9上调。生物信息学分析揭示了过度表达的炎症过程，包括S100 a8/a9和与S100 A8连接的核因子（NF）-κB网络。免疫组织化学显示，在ZD：考克斯-2−/−前胃/舌癌前病变和癌中，S100 A8、其异源二聚体伴侣S100 A9、晚期糖基化终产物（AGEs）受体、NF-κB p65和细胞周期蛋白D1共过表达，这是RAGE-S100 A8/A9炎症通路激活的证据。这些癌中p53的积累表明另外的炎症途径的激活。ZD：考克斯-2−/−小鼠的锌补充逆转了炎症并抑制了致癌作用。因此，ZD激活替代炎症相关的癌症途径，促进肿瘤进展并绕过考克斯-2消融的抗肿瘤作用。这些发现具有重要的临床意义，因为包括锌的联合癌症治疗可能会提高疗效。
Zinc (Zn)-deficiency (ZD) is implicated in the pathogenesis of human oral-esophageal cancers. Previously, we showed that in ZD mice genetic deletion of cyclooxygenase-2 (Cox-2) enhances N-nitrosomethylbenzylamine-induced forestomach carcinogenesis. By contrast, Cox-2 deletion offers protection in Zn-sufficient (ZS) mice. We hypothesize that ZD activates pathways insensitive to COX-2 inhibition, thereby promoting carcinogenesis. This hypothesis is tested in a Cox-2−/− mouse tongue cancer model that mimics pharmacologic blockade of COX-2 by firstly examining transcriptome profiles of forestomach mucosa from Cox-2−/− and wild-type mice on a ZD vs. ZS diet, and secondly investigating the roles of identified markers in mouse forestomach/tongue preneoplasia and carcinomas. In Cox-2−/− mice exposed to the tongue carcinogen 4-nitroquinoline 1-oxide, dietary ZD elicited tongue/esophagus/forestomach carcinomas that were prevented by ZS. The precancerous ZD:Cox-2−/−vs. ZS:Cox-2−/− forestomach had an inflammatory signature with upregulation of the proinflammation genes S100a8 and S100a9. Bioinformatics analysis revealed overrepresentation of inflammation processes comprising S100a8/a9 and an nuclear factor (NF)-κB network with connectivity to S100A8. Immunohistochemistry revealed co-overexpression of S100A8, its heterodimeric partner S100A9, the receptor for advanced glycation end-products (RAGE), NF-κB p65, and cyclin D1, in ZD:Cox-2−/− forestomach/tongue preneoplasia and carcinomas, evidence for the activation of a RAGE-S100A8/A9 inflammatory pathway. Accumulation of p53 in these carcinomas indicated activation of additional inflammatory pathways. Zn-replenishment in ZD:Cox-2−/−mice reversed the inflammation and inhibited carcinogenesis. Thus, ZD activates alternative inflammation-associated cancer pathways that fuel tumor progression and bypass the antitumor effect of Cox-2 ablation. These findings have important clinical implications, as combination cancer therapy that includes Zn may improve efficacy.
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影响因子：
3.5
作者：
Bowcock, AM;Shannon, W;Menter, A
通讯作者：
Menter, A
DOI：
10.1158/1078-0432.ccr-09-0788
发表时间：
2010-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Menter DG;Schilsky RL;DuBois RN
通讯作者：
DuBois RN
影响因子：
13.5
作者：
Nemeth, Julia;Stein, Ilan;Hess, Jochen
通讯作者：
Hess, Jochen
影响因子：
2.6
作者：
Lin, Yung-Song;Lin, Li-Ching;Lin, Shih-Wei
通讯作者：
Lin, Shih-Wei
影响因子：
3.4
作者：
Dawson, S. J.;Michael, M.;Zalcberg, J. R.
通讯作者：
Zalcberg, J. R.