Folate transport gene inactivation in mice increases sensitivity to colon carcinogenesis.

Abstract

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.

• Authors: David W L Ma, Richard H Finnell, Laurie A Davidson, Evelyn S Callaway, Ofer Spiegelstein, Jorge A Piedrahita, J Michael Salbaum, Claudia Kappen, Brad R Weeks, Jill James, Daniel Bozinov, Joanne R Lupton, Robert S Chapkin
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 3 Pg. 887-97 (Feb 01 2005) ISSN: 0008-5472 [Print] United States
• PMID: 15705887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carcinogens
• Carrier Proteins
• Folate Receptors, GPI-Anchored
• Membrane Transport Modulators
• Membrane Transport Proteins
• Receptors, Cell Surface
• Reduced Folate Carrier Protein
• Slc19a1 protein, mouse
• S-Adenosylmethionine
• S-Adenosylhomocysteine
• Azoxymethane

Topics

• Animals
• Azoxymethane
• Carcinogens
• Carrier Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Cell Cycle (genetics)
• Cell Transformation, Neoplastic (chemically induced, genetics, metabolism)
• Colon (metabolism, physiology)
• Colonic Neoplasms (chemically induced, genetics, metabolism)
• Folate Receptors, GPI-Anchored
• Gene Expression Profiling
• Gene Silencing
• Genetic Predisposition to Disease
• Kidney (metabolism, physiology)
• Male
• Membrane Transport Modulators
• Membrane Transport Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oligonucleotide Array Sequence Analysis
• Precancerous Conditions (chemically induced, genetics, metabolism)
• Receptors, Cell Surface (antagonists & inhibitors, biosynthesis, genetics)
• Reduced Folate Carrier Protein
• Reverse Transcriptase Polymerase Chain Reaction
• S-Adenosylhomocysteine (blood, metabolism)
• S-Adenosylmethionine (blood, metabolism)