0001 in risk allele cases and P < 0.0001 in non-risk allele cases; TNIP3: P = 0.050 in risk allele cases and P = 0.026 in non-risk allele cases). Table 4 shows the average expression level of genes in each SNP genotype. Of the Selleckchem Dabrafenib 10 genes, IGF2R was the only gene with an expression level that was significantly lower in the non-risk allele cases than in the risk allele cases (P = 0.012). In this study, the expression of IGF2R varied with the genotype of the SNP, rs6983267, at 8q24, which suggested that the carcinogenesis of CRC associated with diabetes mellitus or metabolic syndrome occurs via loss of IGF2R expression in the non-risk allele of 8q24. Additionally,
we analyzed the association between IGF2R downregulation and diabetes mellitus in 8q24 non-risk allele CRC cases by gene set enrichment analysis.12 First, we divided 85 non-risk allele cases into nine cases with diabetes and 76 cases without diabetes. Although positive correlation was not found in any gene set, negative correlation was observed in nine gene sets including IGF2R related to cancer in diabetic cases. Table 5 shows the nine gene sets. In this study, we investigated the association between the SNP at 8q24 and important genes of environmental risk factors of CRC (diabetes mellitus, hyperlipidemia, and metabolic syndrome) using array-CGH and cDNA microarray. IGF2R
was the only molecule associated with CRC in non-risk allele cases with diabetes in this study. Torin 1 datasheet With respect to the mechanism of colorectal carcinogenesis from diabetes or metabolic syndrome, hyperglycemia, hyperinsulinemia, and insulin
resistance are causal factors of CRC.5 Although it is widely known that IGF1R mediates carcinogenesis of various cancers, including CRC, IGF2R, which encodes a multifunctional protein involved in lysosomal enzyme trafficking, fetal organogenesis, tumor suppression, and cytotoxic T cell-induced apoptosis, has also proven to be associated with cancer. IGF2R is considered a tumor suppressor, and the loss of IGF2R has been described in many human malignancies, including CRC.13 Moreover, selleck compound IGF2R is located at chromosome 6q26, a region that has been shown to be related to insulin resistance and obesity-related metabolic phenotypes.14 In principle, IGF2R downregulation should be validated, but Western blotting could not be performed because of the difficulty of sample collection. However, our data and gene set enrichment analysis indicated a correlation between the genotype of rs6983267 at 8q24 and IGF2R expression level, which is associated with carcinogenesis and diabetes, not in risk allele but non-risk allele cases with diabetes mellitus. This result suggests that the SNP at 8q24 makes diabetes a risk factor for colorectal carcinogenesis via IGF2R especially in non-risk allele cases, even though the way the SNP at 8q24 works on diabetes or the relation of IGF2R to CRC carcinogenesis is not clear.