Effects of dietary folate and aging on gene expression in the colonic mucosa of rats: implications for carcinogenesis.
Folate depletion and aging are risk factors for colorectal cancer. We investigated the effects of folate status and aging on gene expression in the rat colon. Young (weanling) and older (12 month) rats were fed folic acid depleted (0 mg/kg) and supplemented (8 mg/kg) diets for 20 weeks. Gene expression was measured in colonic mucosal scrapings (n = 3 per group) using oligonucleotide arrays (Affymetrix U34A). Folate depletion induced the up-regulation of immune-related genes, urokinase and inducible nitric oxide synthase and the down-regulation of adhesion molecules (protocadherin-4, nidogen and integrin alphaV) and vascular endothelial growth factor in young rats. The abbreviated response to depletion in old rats (62 changes versus 136 in the young) included up-regulation of caspase-2 and deleted in colon cancer. Gene expression changes due to aging were more abundant in folate depleted than supplemented rats (38 versus 119 genes, respectively). In folate-deficient rats, aging induced the down-regulation of immune-related genes, urokinase, p53, insulin-like growth factor binding protein-3 and vav-1 oncogene. In folate supplemented rats, aging induced the down-regulation of vascular endothelial growth factor and caspase-2. Lower expression of adhesion molecules and higher expression of urokinase with folate depletion in young rats may indicate that cell detachment and migration, cancer-related processes, may be modulated by folate status. An age-related decline in p53 and IGF-BP3 expression was only observed in folate depleted animals, indicating that folate supplementation may reduce the risk for age-associated cancers by suppressing deleterious changes in the expression of certain genes.
Crott
Jimmy W
JW
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA. jimmy.crott@tufts.edu
Choi
Sang-Woon
SW
Ordovas
Jose M
JM
Ditelberg
Jeremy S
JS
Mason
Joel B
JB
D000375:Aging; D000818:Animals; D003106:Colon / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D004032:Diet; D005492:Folic Acid / Q000008:administration & dosage*; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D015345:Oligonucleotide Probes; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D015345:Oligonucleotide Probes; D016159:Tumor Suppressor Protein p53; D005492:Folic Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D014568:Urokinase-Type Plasminogen Activator