Reversal of gene expression changes in the colorectal normal-adenoma pathway by NS398 selective COX2 inhibitor.
OBJECTIVE
Treatment of colorectal adenomas with selective cyclooxygenase-2 inhibitors can contribute to the chemoprevention of colorectal cancer (CRC), but the molecular background of their effect is not fully understood. We analysed the gene expression modulatory effect of N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide (NS398) on HT29 cells to be correlated with expression data gained from biopsy samples.


METHODS
HT29 colon adenocarcinoma cells were treated with NS398, and global mRNA expression was analysed on HGU133Plus2.0 microarrays. Discriminatory transcripts between normal and adenoma and between adenoma and CRC biopsy samples were identified using HGU133Plus2.0 microarrays. The results were validated using RT-PCR and immunohistochemistry.


RESULTS
Between normal and adenoma samples, 20 classifiers were identified, including overexpressed cadherin 3, KIAA1199, and downregulated peptide YY, glucagon, claudin 8. Seventeen of them changed in a reverse manner in HT29 cells under NS398 treatment, 14 (including upregulated claudin 8, peptide YY, and downregulated cadherin 3, KIAA1199) at a significance of P<0.05. Normal and CRC could be distinguished using 38 genes, the expression of 12 of them was changed in a reverse manner under NS398 treatment.


CONCLUSIONS
NS398 has a reversal effect on the expression of several genes that altered in colorectal adenoma-carcinoma sequence. NS398 more efficiently inverted the expression changes seen in the normal-adenoma than in the normal-carcinoma transition.
Galamb
O
O
Department of Medicine, Semmelweis University, Budapest, Hungary. orsg1@yahoo.com
Spisák
S
S
Sipos
F
F
Tóth
K
K
Solymosi
N
N
Wichmann
B
B
Krenács
T
T
Valcz
G
G
Tulassay
Z
Z
Molnár
B
B
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D009578:Nitrobenzenes / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D012007:Rectum / Q000187:drug effects / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide