S100A8 and S100A9 are novel nuclear factor kappa b target genes during malignant progression of murine and human liver carcinogenesis

Julia Németh, Ilan Stein, Daniel Haag, Astrid Riehl, Thomas Longerich, Elad Horwitz, Kai Breuhahn, Christoffer Gebhardt, Peter Schirmacher, Meinhard Hahn, Yinon Ben-Neriah, Eli Pikarsky, Peter Angel*, Jochen Hess

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

The nuclear factor-kappaB (NF-κB) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-κB-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-κB-deficient and NF-κB-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-κB 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-κB 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.

Original languageAmerican English
Pages (from-to)1251-1262
Number of pages12
JournalHepatology
Volume50
Issue number4
DOIs
StatePublished - 2009

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