S100A8 and S100A9 Are Novel Nuclear Factor Kappa B Target Genes During Malignant Progression of Murine and Human Liver Carcinogenesis
S100A8 and S100A9 Are Novel Nuclear Factor Kappa B Target Genes During Malignant Progression of Murine and Human Liver Carcinogenesis
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DOI：
10.1002/hep.23099
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发表时间：
2009-10-01
期刊：
影响因子：
13.5
通讯作者：
Hess, Jochen
中科院分区：
文献类型：
--
作者：
Nemeth, Julia;Stein, Ilan;Hess, Jochen
核因子-kappaB(NF-kappaB)信号通路最近被证明参与了炎症诱导的肿瘤进展。在这里，我们描述了在公认的炎症相关肝癌发生的mdr2基因敲除小鼠模型中，对依赖于NF-kappa B的基因调控网络的详细分析。核因子-kappa B缺陷型和核因子-kappaB熟练型肝细胞癌的表达谱显示了包括S100A8和S100A9在内的已知和新的核因子-kappaB靶基因的完整列表。我们检测到S100A8和S100A9蛋白在小鼠肝癌细胞、人肝癌组织和肝癌细胞系Hep3B中的共表达增加。最后，我们发现S100A8和S100A9在Hep3B细胞中具有协同作用，导致显著诱导活性氧自由基(ROS)，并伴随着提高细胞存活率。结论：S100A8和S100A9是炎症相关肝细胞癌变过程中新的核因子-kappaB靶基因，为两种蛋白共同表达增强通过激活ROS依赖的信号通路和保护细胞免于死亡而支持恶性进展提供了实验证据。(《肝病》2009；50：1251-1262。)
The nuclear factor-kappaB (NF-kappa B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-kappa B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-kappa B-deficient and NF-kappa B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-kappa B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-kappa B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)