Selective COX2 inhibitors also seem to be effective for prevention of sporadic adenomatous polyps, as they significantly reduced the occurrence of colorectal adenomas within 3 years after polypectomy (Arber selleck products et al, 2006). However, their use is associated with increased cardiovascular risk (Baron et al, 2006; Bertagnolli et al, 2006). The treatment of CRC patients with selective COX2 inhibitors should be less effective, because increased COX2 expression is present in the earlier phase of colorectal carcinogenesis (Eberhart et al, 1994; Yona and Arber, 2006), but the exact molecular biological reasons in the background of this phenomenon are not clarified yet.
High-throughput screening technologies such as mRNA expression microarrays were applied to find other molecular targets of selective COX2 inhibitors besides COX2, in order to discover the mechanisms explaining their anti-cancer effect in prostate cancer (John-Aryankalayil et al, 2009; Sooriakumaran et al, 2009) and CRC (Zagani et al, 2009). In this study, we analysed the effect of NS398 selective COX2 inhibitor on adenoma- and CRC-associated gene expression profiles in the HT29 colon adenocarcinoma cell line using the whole-genomic HGU133 Plus 2.0 microarray system. The global gene expression modulatory effect of NS398 was also examined to find other target molecules and pathways influenced by NS398 selective COX2 inhibitor treatment in epithelial cells. We found that NS398 has a reverse effect on the expression of genes with altered expression in the colorectal adenoma�Ccarcinoma sequence.
NS398 more efficiently inverted the expression changes at the adenoma than in the carcinoma stage, demonstrating that it is an effective drug in CRC chemoprevention in the early phase of carcinogenesis. We have previously identified CRC and adenoma-specific gene expression marker sets in biopsy samples for diagnostic classification. Although colorectal adenoma and adenocarcinoma are epithelial alterations, the cancer microenvironment and interaction between cancer and stromal cells have critical roles in tumour development and progression. That is why the origin of mRNA expression changes �C identified in biopsy samples containing both epithelial and stromal tissue elements �C was analysed using LCM epithelial samples before model selection. Cilengitide The HT29 colon adenocarcinoma cell line was selected after establishing the fact that most of the above-mentioned markers are epithelium derived. The other reason was that COX2 is decisively expressed in the adenomatous or tumourous epithelium, but there are several studies in which stromal COX2 expression is reported (Nakagawa et al, 2004; Soumaoro et al, 2004).