Abstract
BackgroundRegular aspirin use reduces colon adenoma and carcinoma incidence. UDP-glucuronosyltransferases (UGT) are involved in aspirin metabolism and clearance, and variant alleles in UGT1A6 have been shown to alter salicylic acid metabolism and risk of colon neoplasia.MethodsIn a randomized, cross-over, placebo-controlled trial of 44 healthy men and women, homozygous for UGT1A6*1 or UGT1A6*2, we explored differences between global epithelial and stromal expression, using Affymetrix U133 + 2.0 microarrays and tested effects of 60-day aspirin supplementation (325 mg/d) on epithelial and stromal gene expression and colon prostaglandin E2 (PGE2) levels.ResultsNo statistically significant differences in gene expression were observed in response to aspirin or UGT1A6 genotype, but tissue PGE2 levels were lower with aspirin compared to placebo (p <0.001). Transcripts differentially expressed between epithelium and stroma (N = 4916, P <0.01, false discovery rate <0.001), included a high proportion of genes involved in cell signaling, cellular movement, and cancer. Genes preferentially expressed in epithelium were involved in drug and xenobiotic metabolism, fatty acid and lipid metabolism, apoptosis signaling, and ion transport. Genes preferentially expressed in stroma included those involved in inflammation, cellular adhesion, and extracellular matrix production. Wnt-Tcf4 pathway genes were expressed in both epithelium and stroma but differed by subcellular location.ConclusionsThese results suggest that, in healthy individuals, subtle effects of aspirin on gene expression in normal colon tissue are likely overwhelmed by inter-individual variability in microarray analyses. Differential expression of critical genes between colonic epithelium and stroma suggest that these tissue types need to be considered separately.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0161-6) contains supplementary material, which is available to authorized users.
Highlights
Regular aspirin use reduces colon adenoma and carcinoma incidence
Microarray data are publicly available in Gene Expression Omnibus (GEO) [32]
Forty-two participants were included in the analysis of intervention and UGT1A6 genotype effects (Table 1) and an additional 3 participants with the UGT1A6 *2/*4 genotype were included in the expression array analysis of stromal and epithelial tissue. (Initially, we randomized *2/*4 individuals into the study because the phenotype was thought to be similar to that of *2/*2; with the emergence of new data [38], we decided that the 2 genotypes may be sufficiently different and excluded *2/*4 individuals from the intervention analysis)
Summary
Regular aspirin use reduces colon adenoma and carcinoma incidence. UDP-glucuronosyltransferases (UGT) are involved in aspirin metabolism and clearance, and variant alleles in UGT1A6 have been shown to alter salicylic acid metabolism and risk of colon neoplasia. Aspirin treatment of colon cancer cell lines results in numerous changes in gene expression [7]. Previous studies designed to characterize the separate contributions of colonic stroma and colonic epithelium to carcinogenesis have focused on comparisons of tumor stroma to normal stroma, or tumor tissue to paired surrounding normal tissue [11,12,14,15]. Because these gene expression studies examined biopsy specimens from intact colon that were not dissected before analysis, the results were confounded by the contributions of multiple and heterogeneous cell types to overall expression signatures. To date, there has been no large-scale attempt to compare gene expression in colonic epithelium from normal healthy individuals to that in stroma from the same individuals or to evaluate the effects of potential preventive treatments on these different tissues
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