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. Copyright © 2011 UICC.