Crott Jimmy W, Choi Sang-Woon, Ordovas Jose M, Ditelberg Jeremy S, Mason Joel B
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA.
Carcinogenesis. 2004 Jan;25(1):69-76. doi: 10.1093/carcin/bgg150. Epub 2003 Sep 11.
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.
叶酸缺乏和衰老都是结直肠癌的风险因素。我们研究了叶酸状态和衰老对大鼠结肠基因表达的影响。将幼年（断奶）和老年（12个月）大鼠分别喂食叶酸缺乏（0毫克/千克）和补充（8毫克/千克）的饲料20周。使用寡核苷酸阵列（Affymetrix U34A）检测结肠黏膜刮片（每组n = 3）中的基因表达。叶酸缺乏诱导幼年大鼠免疫相关基因、尿激酶和诱导型一氧化氮合酶上调，以及黏附分子（原钙黏蛋白-4、巢蛋白和整合素αV）和血管内皮生长因子下调。老年大鼠对缺乏的反应减弱（62处变化，幼年大鼠为136处），包括胱天蛋白酶-2上调和结肠癌缺失。与叶酸补充组大鼠相比，叶酸缺乏组大鼠因衰老导致的基因表达变化更为丰富（分别为38个和119个基因）。在叶酸缺乏的大鼠中，衰老诱导免疫相关基因、尿激酶、p53、胰岛素样生长因子结合蛋白-3和vav-1癌基因下调。在叶酸补充的大鼠中，衰老诱导血管内皮生长因子和胱天蛋白酶-2下调。幼年大鼠叶酸缺乏时黏附分子表达降低和尿激酶表达升高，可能表明细胞脱离和迁移（与癌症相关的过程）可能受叶酸状态调节。仅在叶酸缺乏的动物中观察到p53和IGF-BP3表达随年龄下降，这表明补充叶酸可能通过抑制某些基因表达的有害变化来降低与年龄相关癌症的风险。
