Tissue-specific patterns of gene expression in the epithelium and stroma of normal colon in healthy individuals in an aspirin intervention trial.
BACKGROUND
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.


METHODS
In 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.


RESULTS
No 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.


CONCLUSIONS
These 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.
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. ssthomas@fredhutch.org.
Sushma S
SS
Thomas
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. kmakar@fredhutch.org.
Karen W
KW
Makar
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. alex_lee001@yahoo.com.
Lin
L
Li
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. yzheng@fredhutch.org.
Yingye
Y
Zheng
M.D. Anderson Cancer Center, Houston, TX, 77030, USA. pyang@mdanderson.org.
Peiying
P
Yang
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. llevy@fredhutch.org.
Lisa
L
Levy
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. rrudolph7@gmail.com.
Rebecca Yvonne
RY
Rudolph
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. plampe@fredhutch.org.
Paul D
PD
Lampe
Case Western Reserve University School of Medicine, Cincinnati, OH, 44106, USA. yanmin8@hotmail.com.
Min
M
Yan
Case Western Reserve University School of Medicine, Cincinnati, OH, 44106, USA. sxm10@case.edu.
Sanford D
SD
Markowitz
Amgen Corporation, Seattle, WA, 98119, USA. jbigler@amgen.com.
Jeannette
J
Bigler
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. jlampe@fredhutch.org.
Johanna W
JW
Lampe
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. jpotter@fredhutch.org.
John D
JD
Potter
D000328:Adult; D001241:Aspirin / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D060833:Cellular Microenvironment / Q000187:drug effects / Q000235:genetics; D003106:Colon / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D064368:Healthy Volunteers; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity; D004364:Pharmaceutical Preparations / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D015262:Xenobiotics / Q000378:metabolism; D055815:Young Adult
D004364:Pharmaceutical Preparations; D015262:Xenobiotics; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; D015232:Dinoprostone; D001241:Aspirin