Journal
HEPATOLOGY
Volume 50, Issue 4, Pages 1251-1262Publisher
WILEY
DOI: 10.1002/hep.23099
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Funding
- Cooperation in Cancer Research of the Deutsche Krebsforschungszentrum
- Israeli's Ministry of Science, Culture and Sport [Ca-117, Ca-130]
- Helmholtz Association within the Helmholtz Alliance on Systems Biology
- German Ministry for Education and Research (National Genome Research Network) [NGFN-2 01GR0418, 01GS04960]
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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.)
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