Invasion Associated Up-Regulation of Nuclear Factor κB Target Genes in Colorectal Cancer

BACKGROUND: Colorectal cancer (CRC) displays intratumoral heterogeneity with less differentiated tumor cells at the invasive front (IF) than in the tumor center (TC). The authors previously observed that several genes were overexpressed at the IF of CRC with relations to inflammatory processes. Because nuclear factor kappa B (NF-kappa B), a dimeric transcription factor, is a major regulator of such processes, and because its target genes are involved in immune response, cell growth control, and cell survival, the expression of NF-kappa B target genes was investigated comparatively in CRC. METHODS: By using gene array profiling, NF-kappa B target gene expression was assessed in CRCs that expressed human mutL homolog 1 (hMLH1), hMSH2, and nuclear beta-catenin by comparing expression at the IF, in the TC, and in normal mucosa. In addition, 5 NF-kappa B target genes with high differential expression were validated by using immunohistochemistry. RESULTS: The expression of NF-kappa B target genes in the TC, at the IF, and in normal mucosa was distinct; whereas, specifically at the IF, most differentially expressed NF-kappa B targets were up-regulated. Moreover, the results indicated that the expression diverged between epithelial tumor cells and inflammatory stromal cells. CONCLUSIONS: Because the results demonstrated that inflammation and the activation of NF-kappa B signaling promoted CRC invasiveness, the current study provided further evidence that downstream targets of NF-kappa B signaling may be specifically relevant in invasion and progression of CRC. Finally, as has been suggested for colitis-associated cancer, the authors of this report concluded that the inhibition of NF-kappa B signaling also may be an additional option for the treatment of sporadic CRC. Cancer 2009;115:4946-58. (C) 2009 American Cancer Society.