Int J Cancer 2012 Jan;130 (1): 10-9. [IF:4.926]
Inactivation of the vitamin D receptor in APC(min/+) mice reveals a critical role for the vitamin D receptor in intestinal tumor growth.
Zheng W , Wong KE , Zhang Z , Dougherty U , Mustafi R , Kong J , Deb DK , Zheng H , Bissonnette M , Li YC .
Department of General Surgery, Institute of Clinical Medical Research, Hunan Provincial People's Hospital, Changsha, Hunan, China; Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL.
长沙湖南省人民医院普外科研究所，芝加哥大学医学系
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.
摘要：
出现的证据支持维生素D在结直肠癌中的抑制作用。然而，机制仍不清。腺瘤样结肠息肉/β-连蛋白路径在结直肠癌发病机制中起重要作用。我们的研究目的是去探索维生素D和APC/β-连蛋白路径在肠癌发展中的相互作用。遗传性维生素D受体失活的APC(min/+)鼠通过繁殖产生。肠癌发生在不同年龄的APC(min/+) 和APC(min/+) VDR(-/-)鼠间比较。在3,4,6,7,个月的APC(min/+) and APC(min/+) VDR(-/-)鼠间，没观察到小肠和结肠瘤数量的不同。在所有年龄组，APC(min/+) VDR(-/-)鼠的肿瘤大小显著的增加。免疫染色显示，APC(min/+) VDR(-/-)肿瘤与APC(min/+) 肿瘤比较，β-连蛋白, 细胞周期蛋白D1, 磷酸化 Stat-3 and MSH-2 水平显著增加，Stat-1减少。这些观察暗示VDR信号抑制肿瘤生长而不是肠瘤的产生。因此，在APC(min/+) VDR(-/-)鼠肿瘤长的的负担可能是由于VDR生长抑制效应的丧失。研究提供了在肠肿瘤发生中体外显示的维生素D和β-连蛋白信号通路的相互作用的体内相关性的证据。
