Use of a novel genetic mouse model to investigate the role of folate in colitis-associated colon cancer

作者：Chapkin Robert S^*; Kamen Barton A; Callaway Evelyn S; Davidson Laurie A; George Nysia I; Wang Naisyin; Lupton Joanne R; Finnell Richard H

来源：Journal of Nutritional Biochemistry, 2009, 20(8): 649-655.

DOI：10.1016/j.jnutbio.2008.07.001

• Inflammatory bowel disease
• Mouse models
• Azoxymethane
• Dextran sodium sulphate
• Folate-binding protein
• Reduced folate carrier

Inflammatory bowel disease (IBD) patients are at high fisk for developing folate deficiency and colon cancer. Since it is difficult to study the subtle global and gene-specific epigenetic mechanisms involved in folate-mediated tumor initiation and promotion, we have generated genetically modified mouse models by targeting the reduced folate carrier (RFC1) and folate-binding protein (Folbp1) genes. The transgenic mice were fed semi-purified diets for 8 weeks containing either normal (2 mg) or deficient (0.1 mg folate/kg diet) levels of folate. Compound heterozygous mice (Folbp1( /-); RFC1( /-)) fed an adequate folate diet exhibited a reduction in plasma folate concentrations compared to heterozygous (Folbp1( /-)) and littermate wild-type mice (P<05). In contrast, no differences were observed in colonic mucosa. Consumption of a low folate diet significantly reduced (three- to fourfold) plasma and tissue folate levels in all animal models, although plasma homocysteine levels were not altered. In order to elucidate the relationship between folate status and inflammation-associated colon cancer, animals were injected with azoxymethane followed by dextran sodium sulphate treatment in the drinking water. Mice were fed a normal folate diet and were terminated 5 weeks after carcinogen injection. The number of high multiplicity aberrant crypt foci per centimeter of colon was significantly elevated (P<05) in compound Folbp1( /-); RFC1( /-) (3.5 /- 0.4) mice as compared to Folbp1( /-) (1.9 /- 0.3) and wild-type control mice (1.1 /- 0.1). These data demonstrate that the ablation of two receptor/carrier-mediated pathways for folate transport increases the risk for developing inflammation-associated colon cancer.

• 出版日期2009-8