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

Abstract

The nuclear factor-kappaB (NF-B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-B-deficient and NF-B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-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-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.)H epatocellular carcinoma (HCC) is the most frequent type of liver cancer and one of the most prevalent causes of cancer mortality worldwide. These tumors arise at sites of chronic liver injury, inflammation, and hepatocyte proliferation provoked by several causes such as chronic hepatitis B and C viral infection, chronic alcohol consumption, and aflatoxin B1-contaminated food. 1,2 Despite remarkable improvements in diagnosis, only limited therapeutic options exist, most of them with minimal clinical benefit. 2 Moreover, there is

Oncogenic Kras Expression in Postmitotic Neurons Leads to S100A8-S100A9 Protein Overexpression and Gliosis

“…Indeed, gene set enrichment analysis of our microarray results reveals that glioma-associated genes are significantly enriched among genes differentially expressed in the Kras G12D mutant cortex. S100A8 and S100A9 Play Dual Functions in Kras G12D-induced Gliosis-Our data suggest that S100A8 and S100A9 act as both growth factors to promote primary astrocyte growth and chemokines to induce the infiltration of myeloid cells to the cortex, consistent with the dual role of these molecules in inflammation-associated cancer (52). The growth-promoting activity of S100A8-S100A9 on various human cancer cells was previously documented (31,53).…”

S100A8 and S100A9: New Insights into Their Roles in Malignancy

“…Expression in keratinocytes and in hepatocellular tumor cells is also promoted by activation of NF-B, while AP-1 appears to negatively regulate expression in keratinocytes [9,20] . In addition, STAT-3 promotes transcriptional activation of S100A9 in myeloid progenitors and breast cancer cells [9,14] .…”

New Insights into the Regulation of Neutrophil NADPH Oxidase Activity in the Phagosome: A Focus on the Role of Lipid and Ca2+Signaling

“…This signaling contributes to the activation of p38 MAPK and the downstream effector NFjB (29). S100A8 and S100A9 have recently been identified as target genes of NF-jB (76), which regulate their expression, thus allowing them to fulfill their intracellular roles (Fig. 8).…”