[SFRP, a family of new colorectal tumor suppressor candidate genes].
Aberrant Wnt pathway signaling is an early progression event in up to 90% of colorectal cancers (CRC). It occurs mainly through mutations of APC or beta-catenin. We have identified frequent promoter hypermethylation and gene silencing of the secreted frizzled-related protein (SFRP) genes in CRC. SFRPs possess a domain similar to one in the Wnt receptor Frizzled proteins and can inhibit Wnt receptor binding to downregulate pathway signaling in development. We next found that restoration of SFRP function in CRC cells attenuates Wnt signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in CRC progression and may, thus, provide constitutive Wnt signaling which is required to complement downstream mutations in the evolution of CRC.
Suzuki
Hiromu
H
First Department of Internal Medicine, Sapporo Medical University.
Toyota
Minoru
M
Nojima
Masanori
M
Mori
Mitsuru
M
Imai
Kohzoh
K
D015179:Colorectal Neoplasms / Q000235:genetics*; D016153:Genes, Suppressor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008745:Methylation; D011506:Proteins / Q000235:genetics*; D051153:Wnt Proteins; D000099274:Frizzled-Related Proteins
D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D051153:Wnt Proteins; D000099274:Frizzled-Related Proteins