Zinc replenishment reverses overexpression of the proinflammatory mediator S100A8 and esophageal preneoplasia in the rat.
Zinc replenishment reverses overexpression of the proinflammatory mediator S100A8 and esophageal preneoplasia in the rat.
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DOI：
10.1053/j.gastro.2008.11.039
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发表时间：
2009-03
期刊：
影响因子：
29.4
通讯作者：
Fong LY
中科院分区：
文献类型：
--
作者：
Taccioli C;Wan SG;Liu CG;Alder H;Volinia S;Farber JL;Croce CM;Fong LY
缺锌与人类食道癌的发病机制有关。在大鼠食管中，它诱导细胞增殖，调节基因表达，并增强致癌作用。锌补充逆转增殖和抑制致癌作用。缺锌大鼠模型允许识别早期食管癌发生过程中受锌影响的生物学差异。我们评估了食管上皮细胞的基因表达谱缺锌和补充与充足的大鼠使用Affyssin大鼠基因组基因芯片。我们的特点是顶部上调基因S100 A8在食管增生/逆转和化学诱导的食管癌发生在锌调节动物的免疫组化和实时定量聚合酶链反应的作用。增生缺陷型食管具有独特的表达特征，促炎基因S100 A8和S100 A9上调57倍和5倍。包含S100 A8的“对外部刺激的反应”是上调基因中唯一显著过度表达的生物学途径。锌补充迅速恢复到控制水平的S100 A8/A9和其他27个基因的表达和逆转增生表型。在NF-κB p65和考克斯-2蛋白过表达的缺陷型食管中，S100 A8蛋白与其受体发生共定位和过表达。补充锌而不是考克斯-2抑制剂减少了这4种蛋白的过度表达。此外，食管S100 A8/A9 mRNA水平与缺锌和补锌大鼠的不同致瘤结果直接相关。体内锌调节S100 A8表达并调节S100 A8-β相互作用与下游NF-κB/考克斯-2信号传导之间的联系。锌调节食管癌发生中的炎症通路的发现可能导致这种癌症的预防和治疗。
Zinc-deficiency is implicated in the pathogenesis of human esophageal cancer. In the rat esophagus, it induces cell proliferation, modulates genetic expression, and enhances carcinogenesis. Zinc-replenishment reverses proliferation and inhibits carcinogenesis. The zinc-deficient rat model allows the identification of biological differences affected by zinc during early esophageal carcinogenesis. We evaluated gene expression profiles of esophageal epithelia from zinc-deficient and replenished rats versus sufficient rats using Affymetrix Rat Genome GeneChip. We characterized the role of the top-upregulated gene S100A8 in esophageal hyperplasia/reversal and in chemically-induced esophageal carcinogenesis in zinc-modulated animals by immunohistochemistry and real-time quantitative polymerase chain reaction. The hyperplastic deficient esophagus has a distinct expression signature with the proinflammation-gene S100A8 and S100A9 upregulated 57- and 5-fold. “Response to external stimulus” comprising S100A8 was the only significantly overrepresented biological pathway among the upregulated genes. Zinc-replenishment rapidly restored to control levels the expression of S100A8/A9 and 27 other genes and reversed the hyperplastic phenotype. With its receptor RAGE, co-localization and overexpression of S100A8 protein occurred in the deficient esophagus that overexpressed NF-κB p65 and COX-2 protein. Zinc-replenishment but not by a COX-2 inhibitor reduced the overexpression of these 4 proteins. Additionally, esophageal S100A8/A9 mRNA levels were directly associated with the diverse tumorigenic outcome in zinc-deficient and zinc-replenished rats. In vivo zinc regulates S100A8 expression and modulates the link between S100A8-RAGE interaction and downstream NF-κB/COX-2 signaling. The finding that zinc regulates an inflammatory pathway in esophageal carcinogenesis may lead to prevention and therapy for this cancer.
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影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P
影响因子：
9.7
作者：
Bharadwaj, S;Prasad, GL
通讯作者：
Prasad, GL
DOI：
10.1073/pnas.251532498
发表时间：
2001-11-20
影响因子：
11.1
作者：
Blanchard, RK;Moore, JB;Cousins, RJ
通讯作者：
Cousins, RJ
影响因子：
4.7
作者：
Fong, LYY;Li, JX;Magee, PN
通讯作者：
Magee, PN
影响因子：
6.4
作者：
Kumar, Anupam;Chatopadhyay, Tusharkant;Ralhan, Ranju
通讯作者：
Ralhan, Ranju