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Hedgehog and WNT signaling pathways network together during embryogenesis and carcinogenesis. Hedgehog signaling in intestinal epithelium represses canonical WNT signaling to restrict expression of WNT target genes to stem or progenitor cells; however, the mechanism remains unclear. The Hedgehog signal is transduced to GLI family transcription factors though Patched receptor, Smoothened signal transducer, and other signaling components, such as KIF27, KIF7, STK36, SUFU, and DZIP1. Here, we searched for the GLI-binding site within the promoter region of genes encoding secretedtype WNT signal inhibitors, including SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4, and WIF1. The GLI-binding site was identified within the human SFRP1 promoter based on bioinformatics and human intelligence. The chimpanzee SFRP1 gene was identified within the NW_110515.1 genome sequence. The GLI-binding site of the human SFRP1 promoter was conserved in chimpanzee SFRP1, mouse Sfrp1, and rat Sfrp1 promoters. SFRP1 is the evolutionarily conserved target of the Hedgehog-GLI signaling pathway. Expression domain analyses based on text mining revealed that Indian Hedgehog (IHH), SFRP1, and WNT6 are expressed in differentiated intestinal epithelial cells, mesenchymal cells, and stem/progenitor cells, respectively. Hedgehog is secreted from differentiated epithelial cells to induce SFRP1 expression in mesenchymal cells, which keeps differentiated epithelial cells away from the effects of canonical WNT signaling. These facts indicate that SFRP1 is the Hedgehog target to confine canonical WNT signaling within stem or progenitor cells. Therefore, epigenetic CpG hypermethylation of the SFRP1 promoter during chronic persistent inflammation and aging leads to the occurrence of gastrointestinal cancers, such as colorectal cancer and gastric cancer, through the breakdown of Hedgehog-dependent WNT signal inhibition. Introduction The Hedgehog signaling pathway is implicated in embryogenesis and carcinogenesis (1-3). Sonic Hedgehog (SHH), Indian Hedgehog (IHH) and Desert Hedgehog (DHH) are Hedgehog family ligands (4-6). PTCH1, PTCH2, DISP1, DISP2 and DISP3 are multi-transmembrane proteins sharing two PTCH/ DISP homologous domains (7,8). PTCH1 and PTCH2 are Hedgehog receptors while seven-transmembrane protein, Smoothened (SMO), is the Hedgehog signal transducer (9-13). KIF27, KIF7, STK36, SUFU, and DZIP1 are Hedgehog signaling components (10-17). GLI1, GLI2, and GLI3 are GLI family transcription factors to activate the transcription of Hedgehog target genes (1,18). PTCH1, CCND2, IGFBP6, and FOXM1 genes are direct transcriptional targets of the Hedgehog-GLI signaling pathway (19,20). Hedgehog and WNT signaling pathways network together during embryogenesis and carcinogenesis (1). Hedgehog signaling in intestinal epithelium represses canonical WNT signaling to restrict expression of WNT target genes to stem or progenitor cells (2); however, the mechanism remains unclear. Induction of the secreted-type WNT inhibitor by the Hedgehog signaling pathway is one reasonable explanation for the Hedgehog-dependent WNT signal inhibition. SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4, and WIF1 genes encode secreted-type WNT inhibitors (21-27). We have previously reported comparative genomics analyses on SFRP1, SFRP2, DKK1, DKK2, and DKK4 orthologs (24-27). Here, we searched for GLI-binding site within the promoter region of WNT inhibitor genes. The SFRP1 gene was identified as the evolutionarily conserved target of the Hedgehog-GLI signaling pathway. Materials and methods Hedgehog target gene screening. Genome sequences corresponding to human SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4 and WIF1 genes were searched for using BLAST programs (http://www.ncbi.nlm.nih.gov) as described previously (28,29). GLI-binding sites within the 5'-flanking promoter region of above genes were searched for based on bioinformatics and human intelligence. Identification of chimpanzeee SFRP1 ortholog. Chipmanzee genome sequences homologous to human SFRP1 were searched for using BLAST programs as described previously INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 17: 171-175, 2006 171 WNT antagonist, SFRP1, is Hedgehog signaling target YURIKO KATOH1 and MASARU KATOH2 1M&M Medical BioInformatics, Hongo 113-0033; 2Genetics and Cell Biology Section, National Cancer Center Research Institute, Tokyo 104-0045, Japan Received September 26, 2005; Accepted October 31, 2005 _________________________________________ Correspondence to: Dr Masaru Katoh, Genetics and Cell Biology Section, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan E-mail: [email protected]