Comprehensive analysis of ß-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/ß-catenin signaling.

ABSTRACT

BACKGROUND: Deregulation of Wnt/ß-catenin signaling is a hallmark of the majority of sporadic forms of colorectal cancer and results in increased stability of the protein ß-catenin. ß-catenin is then shuttled into the nucleus where it activates the transcription of its target genes, including the proto-oncogenes MYC and CCND1 as well as the genes encoding the basic helix-loop-helix (bHLH) proteins ASCL2 and ITF-2B. To identify genes commonly regulated by ß-catenin in colorectal cancer cell lines, we analyzed ß-catenin target gene expression in two non-isogenic cell lines, DLD1 and SW480, using DNA microarrays and compared these genes to ß-catenin target genes published in the PubMed database and DNA microarray data presented in the Gene Expression Omnibus (GEO) database. RESULTS: Treatment of DLD1 and SW480 cells with ß-catenin siRNA resulted in differential expression of 1501 and 2389 genes, respectively. 335 of these genes were regulated in the same direction in both cell lines. Comparison of these data with published ß-catenin target genes for the colon carcinoma cell line LS174T revealed 193 genes that are regulated similarly in all three cell lines. The overlapping gene set includes confirmed ß-catenin target genes like AXIN2, MYC, and ASCL2. We also identified 11 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are regulated similarly in DLD1 and SW480 cells and one pathway - the steroid biosynthesis pathway - was regulated in all three cell lines. CONCLUSIONS: Based on the large number of potential ß-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T cells as well as the large overlap with confirmed ß-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study Wnt/ß-catenin signaling and associated colorectal carcinogenesis. Furthermore, the confirmed and the newly identified potential ß-catenin target genes are useful starting points for further studies.