Inactivation of the vitamin D receptor in APCmin/+ mice reveals a critical role for the vitamin D receptor in intestinal tumor growth

✍ Scribed by Wei Zheng; Kari E. Wong; Zhongyi Zhang; Urzsula Dougherty; Reba Mustafi; Juan Kong; Dilip K. Deb; Huachuan Zheng; Marc Bissonnette; Yan Chun Li

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: French
• Weight: 910 KB
• Volume: 130
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.25992

✦ Synopsis

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.