title: Inactivation of the vitamin D receptor in APC(min/+)  mice reveals a critical role for the vitamin D receptor in intestinal tumor growth.
abstract: Emerging evidence supports an inhibitory role for vitamin D in colorectal carcinogenesis; however, the mechanism remains unclear. The adenomatous polyposis coli (APC)/β-catenin pathway plays a critical role in colorectal carcinogenesis. The purpose of our study is to explore the interactions of vitamin D and APC/β-catenin pathways in intestinal tumor development. APC(min/+)  mice with genetic inactivation of the vitamin D receptor (VDR) were generated through breeding. Intestinal tumorigenesis was compared between APC(min/+)  and APC(min/+) VDR(-/-)  mice at different ages. No differences were seen in the number of small intestinal and colonic tumors between APC(min/+)  and APC(min/+) VDR(-/-)  mice aged 3, 4, 6 and 7 months. The size of the tumors, however, was significantly increased in APC(min/+) VDR(-/-)  mice in all age groups. Immunostaining showed significant increases in β-catenin, cyclin D1, phosphorylated Stat-3 and MSH-2 levels and decreases in Stat-1 in APC(min/+) VDR(-/-)  tumors compared to APC(min/+)  tumors. These observations suggest that VDR signaling inhibits tumor growth rather than tumor initiation in the intestine. Thus, the increased tumor burden in APC(min/+) VDR(-/-)  mice is likely due to the loss of the growth-inhibiting effect of VDR. This study provides strong evidence for the in vivo relevance of the interaction demonstrated in vitro between the vitamin D and β-catenin signaling pathways in intestinal tumorigenesis.
authors.affiliation: Department of General Surgery, Institute of Clinical Medical Research, Hunan Provincial People's Hospital, Changsha, Hunan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Kari E
authors.initials: KE
authors.lastname: Wong
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Urzsula
authors.initials: U
authors.lastname: Dougherty
authors.forename: Reba
authors.initials: R
authors.lastname: Mustafi
authors.forename: Juan
authors.initials: J
authors.lastname: Kong
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Deb
authors.forename: Huachuan
authors.initials: H
authors.lastname: Zheng
authors.forename: Marc
authors.initials: M
authors.lastname: Bissonnette
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017491:Genes, APC / Q000502:physiology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D051176:beta Catenin