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/-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/-catenin pathway and can downregulate -catenin signaling by competing with Wnt ligands for binding to Frizzled receptors, as well as by inhibition of the Akt-GSK-3 (Akt-glycogen synthase kinase-3) pathway. We have shown that both Wnt and nuclear factor-B (NF-B) signaling were boosted in tumor tissues of Apc Olfm4 double-mutant mice. These data establish OLFM4 as a critical negative regulator of the Wnt/-catenin and NF-B 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

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U.S. National Heart Lung and Blood Inst
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Liu, Wenli; Liu, Yueqin; Li, Hongzhen et al. (2018) Olfactomedin 4 contributes to hydrogen peroxide-induced NADPH oxidase activation and apoptosis in mouse neutrophils. Am J Physiol Cell Physiol 315:C494-C501
Liu, Wenli; Rodgers, Griffin P (2016) Olfactomedin 4 expression and functions in innate immunity, inflammation, and cancer. Cancer Metastasis Rev 35:201-12
Liu, W; Li, H; Hong, S-H et al. (2016) Olfactomedin 4 deletion induces colon adenocarcinoma in Apc(Min/+) mice. Oncogene :
Liu, Wenli; Yan, Ming; Sugui, Janyce A et al. (2013) Olfm4 deletion enhances defense against Staphylococcus aureus in chronic granulomatous disease. J Clin Invest 123:3751-5
Liu, Wenli; Yan, Ming; Liu, Yueqin et al. (2012) Olfactomedin 4 inhibits cathepsin C-mediated protease activities, thereby modulating neutrophil killing of Staphylococcus aureus and Escherichia coli in mice. J Immunol 189:2460-7
Liu, Wenli; Lee, Hyun Woo; Liu, Yueqin et al. (2010) Olfactomedin 4 is a novel target gene of retinoic acids and 5-aza-2'-deoxycytidine involved in human myeloid leukemia cell growth, differentiation, and apoptosis. Blood :
Liu, Wenli; Yan, Ming; Liu, Yueqin et al. (2010) Olfactomedin 4 down-regulates innate immunity against Helicobacter pylori infection. Proc Natl Acad Sci U S A 107:11056-61
Liu, Wenli; Liu, Yueqin; Zhu, Jianqiong et al. (2008) Reduced hGC-1 protein expression is associated with malignant progression of colon carcinoma. Clin Cancer Res 14:1041-9
Chin, Kyung L; Aerbajinai, Wulin; Zhu, Jiangqiong et al. (2008) The regulation of OLFM4 expression in myeloid precursor cells relies on NF-kappaB transcription factor. Br J Haematol :