WNT antagonist, SFRP1, is Hedgehog signaling target

Abstract

Abstract. 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.

Accumulation of Hedgehog-Responsive Progenitors Parallels Alcoholic Liver Disease Severity in Mice and Humans

“…30 Interestingly, induction of Sonic hedgehog ligand and the Hh signaling components Ptc and Gli-2 was greater in EtOH-fed mice than HF controls, whereas EtOH consumption did not potentiate HF diet-associated increases in Frp-1.…”

“…This involves increased expression of Hh target genes, including the Wnt inhibitor Frp-1. 30 Canonical Wnt signaling is required for hepatocyte proliferation. 50 Therefore, Frp-1-mediated inhibition of this process is predicted to restrict proliferation of mature hepatocytes, providing a further growth advantage for the immature and fibroblastic liver cells and helping to explain why growth of the latter 2 cell populations is inversely related to that of mature hepatocytes in damaged livers.…”

The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma

“…Maintained SFRP1 expression in the SHH subgroup may be owing to the fact that SFRP1 is a known SHH signaling target (Katoh and Representative SFRP1 expression by an unmethylated MB specimen is included for comparison. Katoh, 2006). SFRP1 expression is seen in both human MB and murine models of MB in which SHH signaling is upregulated (Lee et al, 2003;Thompson et al, 2006;Kool et al, 2008).…”

Hedgehog signaling pathway and gastrointestinal stem cell signaling network (Review)

“…Hedgehog signaling inhibits the canonical WNT signaling and proliferation in intestinal epithelial cells (43). Hedgehog-dependent induction of WNT antagonist SFRP1 in mesenchymal cells partially explains the separation of the Hedgehog signaling activation domain from the WNT signaling activation domain (44).…”