期刊
GASTROENTEROLOGY
卷 144, 期 2, 页码 381-391出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2012.10.048
关键词
Mouse Model of Colon Cancer; beta-Catenin; TCF; Tnfrsf19
资金
- qChIP/chip06 project from the Ministry of Education, Youth and Sports of the Czech Republic [B06077]
- Grant Agency of the Czech Republic [P305/11/1780, P304/11/1252, 204/09/H058, P305/10/2143]
- Grant Agency of Charles University in Prague [43-251452]
- Academy of Sciences of the Czech Republic [RVO 68378050, KAN200520801]
- Third Faculty of Medicine, Charles University in Prague research project [UNCE204010]
- project BIOCEV [CZ.1.05/1.1.00/02.0109]
- IKEM MZO [00023001]
BACKGROUND & AIMS: The Wnt signaling pathway is required for maintenance of the intestinal epithelia; blocking this pathway reduces the proliferative capacity of the intestinal stem cells. However, aberrant Wnt signaling leads to intestinal cancer. We investigated the roles of the Wnt pathway in homeostasis of the intestinal epithelium and during malignant transformation in human cells and mice. METHODS: We performed chromatin immunoprecipitation (ChIP) with DNA microarray analysis (ChIP-on-chip) to identify genes regulated by Wnt signaling in human colorectal cancer cells Colo320, DLD1, LS174T, and SW480. Formation of intestinal tumor was induced in C57BL/6J mice using azoxymethane and dextran sulfate. Intestinal tissues from these mice, as well as Apc(+/Min) and Apc(CKO/CKO)/Lgr5-EGFP-IRES-CreERT2 mice, were analyzed by immunohistochemistry and in situ hybridization. RESULTS: We identified promoter regions of 960 genes that interacted with the Wnt pathway nuclear effector T-cell factor 4 in 4 different human colorectal cancer-derived cell lines; 18 of these promoters were present in all chromatin precipitates. Wnt signaling up-regulated a member of the tumor necrosis factor receptor superfamily called TROY. Levels of TROY messenger RNA were increased in human cells with deficiencies in the adenomatous polyposis coli (APC) gene and in cells stimulated with the Wnt3a ligand. Expression of Troy was significantly up-regulated in neoplastic tissues from mice during intestinal tumorigenesis. Lineage tracing experiments revealed that Troy is produced specifically by fast-cycling intestinal stem cells. TROY associated with a unique marker of these cells, leucine-rich repeat-containing G-protein coupled receptor (LGR) 5. In organoids established from the intestinal crypts, Troy suppressed signaling mediated by R-spondin, a Wnt agonist. CONCLUSIONS: TROY is up-regulated in human colorectal cancer cell lines and in intestinal tumors in mice. It functions as a negative modulator of the Wnt pathway in LGR5-positive stem cells.
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