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Folate Transport Gene Inactivation in Mice Increases Sensitivity to Colon Carcinogenesis

¹ Molecular and Cell Biology Section, Faculty of Nutrition, ² Center for Environmental and Rural Health, ³ Department of Veterinary Anatomy and Public Health, and ⁴ Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas; ⁵ Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas; ⁶ Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina; ⁷ S.C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona; and ⁸ Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Requests for reprints: Robert S. Chapkin, Molecular and Cell Biology Section, Faculty of Nutrition, Texas A&M University, Kleberg Center, TAMU 2471, College Station, TX 77843-2471. Phone: 979-845-0448; Fax: 979-862-2662; E-mail: r-chapkin{at}tamu.edu.

Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding protein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation, gene expression, and colon carcinogenesis. Targeted deletion of Folbp1 (Folbp1^+/– and Folbp1^–/–) significantly reduced (P < 0.05) colonic Folbp1 mRNA, colonic mucosa, and plasma folate concentration. In contrast, subtle changes in folate homeostasis resulted from targeted deletion of RFC1 (RFC1^+/–). These animals had reduced (P < 0.05) colonic RFC1 mRNA and exhibited a 2-fold reduction in the plasma S-adenosylmethionine/S-adenosylhomocysteine. Folbp1^+/– and Folbp1^–/– mice had larger crypts expressed as greater (P < 0.05) numbers of cells per crypt column relative to Folbp1^+/+ mice. Colonic cell proliferation was increased in RFC1^+/– mice relative to RFC1^+/+ mice. Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation. The effect of folate transporter gene ablation on colon carcinogenesis was evaluated 8 and 38 weeks post-azoxymethane injection in wild-type and heterozygous mice. Relative to RFC1^+/+ mice, RFC1^+/– mice developed increased (P < 0.05) numbers of aberrant crypt foci at 8 weeks. At 38 weeks, RFC1^+/– mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1^+/+ mice. In contrast, Folbp1^+/– mice developed 4-fold (P < 0.05) more lesions relative to Folbp1^+/+ mice. In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development.

Key Words: folate • folate binding protein • reduced folate carrier • colon • cancer

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