title: Olfactomedin 4 deletion induces colon adenocarcinoma in ApcMin/+mice.
abstract: Colon carcinogenesis is a multiple-step process involving the accumulation of a series of genetic and epigenetic alterations. The most commonly initiating event of intestinal carcinogenesis is mutation of the adenomatous polyposis coli (APC) gene, which leads to activation of the Wnt/β-catenin pathway. Olfactomedin 4 (OLFM4) has emerged as an intestinal stem-cell marker, but its biological function in the intestine remains to be determined. Here we show that Olfm4 deletion induced colon adenocarcinoma in the distal colon of ApcMin/+mice. Mechanistically, we found that OLFM4 is a target gene of the Wnt/β-catenin pathway and can downregulate β-catenin signaling by competing with Wnt ligands for binding to Frizzled receptors, as well as by inhibition of the Akt-GSK-3β (Akt-glycogen synthase kinase-3β) pathway. We have shown that both Wnt and nuclear factor-κB (NF-κB) signaling were boosted in tumor tissues of Apc Olfm4 double-mutant mice. These data establish OLFM4 as a critical negative regulator of the Wnt/β-catenin and NF-κB pathways that inhibits colon-cancer development initiated by APC mutation. In addition, Olfm4 deletion significantly enhanced intestinal-crypt proliferation and inflammation induced by azoxymethane/dextran sodium sulfate. Thus, OLFM4 has an important role in the regulation of intestinal inflammation and tumorigenesis, and could be a potential therapeutic target for intestinal malignant tumors. Unlike the human colonic epithelium, the mouse colonic epithelium does not express OLFM4, but nevertheless, systemic OLFM4 deletion promotes colon tumorigenesis and that loss from mucosal neutrophils may have a role to play.
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.|Cancer Genomics Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Piszczek
authors.affiliation: Genomic Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Rodgers
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D009154:Mutation; D017384:Sequence Deletion / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D006023:Glycoproteins; D051176:beta Catenin; C584470:olfactomedin 4, mouse