title: 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.affiliation: Molecular and Cell Biology Section, Faculty of Nutrition, Texas A&M University, Kleberg Center, College Station, TX 77843-2471, USA.
authors.forename: David W L
authors.initials: DW
authors.lastname: Ma
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Davidson
authors.forename: Evelyn S
authors.initials: ES
authors.lastname: Callaway
authors.forename: Ofer
authors.initials: O
authors.lastname: Spiegelstein
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Piedrahita
authors.forename: J Michael
authors.initials: JM
authors.lastname: Salbaum
authors.forename: Claudia
authors.initials: C
authors.lastname: Kappen
authors.forename: Brad R
authors.initials: BR
authors.lastname: Weeks
authors.forename: Jill
authors.initials: J
authors.lastname: James
authors.forename: Daniel
authors.initials: D
authors.lastname: Bozinov
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Lupton
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
mesh_terms: D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000502:physiology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D058973:Folate Receptors, GPI-Anchored; D020869:Gene Expression Profiling; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D007668:Kidney / Q000378:metabolism / Q000502:physiology; D008297:Male; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D058978:Reduced Folate Carrier Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012435:S-Adenosylhomocysteine / Q000097:blood / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000097:blood / Q000378:metabolism
chemical_list: D002273:Carcinogens; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; C548700:Slc19a1 protein, mouse; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D001397:Azoxymethane