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.

From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer

“…FOLR1 (folic acid receptor 1), also known as folic acid receptor α and folate-binding protein, is a glycosylphosphatidylinositol junction protein 192 that is closely related to tumor progression and cell proliferation. 193,194 It is overexpressed in the tumors of ovarian, breast, colorectal, kidney, lung, and other solid tumors, and is present at low levels in normal cells. 195,196 As reported, FOLR1 is highly expressed in about one-third of patients with GC, and FOLR1-CAR-T cells have exhibited high anti-cancer activity in preclinical studies.…”