Intestinal Neoplasia Induced by Low Dietary Folate Is Associated with Altered Tumor Expression Profiles and Decreased Apoptosis in Mouse Normal Intestine

Epidemiological studies suggest that low dietary folate increases risk for intestinal neoplasia. We recently developed a unique tumor model in which mice fed low dietary folate developed DNA damage and intestinal tumors. To identify additional mechanisms by which reduced folate intake contributes to tumor formation in this model, we characterized gene expression signatures in tumors. A total of 175 probe sets had altered expression, with the majority (173) showing increased expression compared with normal intestine. Functional categorization revealed that most genes were involved in cancer (51 genes) or cell death (37 genes); 31 genes appeared in both categories. Because apoptosis resistance is a hallmark of neoplasia, we assessed apoptosis in normal intestine of mice fed control (CD) and low-folate diets (FD); apoptosis was reduced in FD normal intestine compared with CD intestine by active caspase-3 expression (P = 0.027) and caspase-3/7 activities (P = 0.059). We selected candidate genes with antiapoptotic properties that had increased expression in tumor microarrays, CD44, and gelsolin and confirmed these increases at the mRNA and protein levels. CD44 and gelsolin protein also increased in mice fed the FD compared with the CID, normal intestine. Bcl-2-like 1:Bcl-2-antagonist/killer 1 mRNA ratios tended to be greater in FD than in CID normal intestine (P = 0.056). In conclusion, tumors induced by low dietary folate exhibited gene expression profiles that are characteristic of disrupted apoptosis. Folate depletion in normal intestine may trigger neoplasia through increased DNA damage and defective apoptosis; upregulation of CD44 and gelsolin, and the mitochondrial apoptotic pathway are implicated. J. Nutr. 139: 488-494, 2009.