Intestinal PTGS2 mRNA Levels, PTGS2 Gene Polymorphisms, and Colorectal Carcinogenesis

Abstract

<div><p>Background & Aims</p><p>Inflammation is a major risk factor for development of colorectal cancer (CRC). Prostaglandin synthase cyclooxygenase-2 (COX-2) encoded by the <i>PTGS2</i> gene is the rate limiting enzyme in prostaglandin synthesis and therefore plays a distinct role as regulator of inflammation.</p><p>Methods</p><p><i>PTGS2</i> mRNA levels were determined in intestinal tissues from 85 intestinal adenoma cases, 115 CRC cases, and 17 healthy controls. The functional <i>PTGS2</i> polymorphisms A-1195G (rs689466), G-765C (rs20417), T8473C (rs5275) were assessed in 200 CRC cases, 991 adenoma cases and 399 controls from the Norwegian KAM cohort.</p><p>Results</p><p><i>PTGS2</i> mRNA levels were higher in mild/moderate adenoma tissue compared to morphologically normal tissue from the same individual (P<0.0001) and (P<0.035) and compared to mucosa from healthy individuals (P<0.0039) and (P<0.0027), respectively. In CRC patients, <i>PTGS2</i> mRNA levels were 8–9 times higher both in morphologically normal tissue and in cancer tissue, compared to healthy individuals (P<0.0001). <i>PTGS2</i> A-1195G variant allele carriers were at reduced risk of CRC (odds ratio (OR) = 0.52, 95% confidence interval (95% CI): 0.28–0.99, P = 0.047). Homozygous carriers of the haplotype encompassing the A-1195G and G-765C wild type alleles and the T8473C variant allele <i>(PTGS2</i> AGC) were at increased risk of CRC as compared to homozygous carriers of the <i>PTGS2</i> AGT (<u>A</u>-1195G, <u>G</u>-765C, <u>T</u>8473C) haplotype (OR = 5.37, 95% CI: 1.40–20.5, P = 0.014). No association between the investigated polymorphisms and <i>PTGS2</i> mRNA levels could be detected.</p><p>Conclusion</p><p>High intestinal <i>PTGS2</i> mRNA level is an early event in colorectal cancer development as it occurs already in mild/moderate dysplasia. <i>PTGS2</i> polymorphisms that have been associated with altered <i>PTGS2</i> mRNA levels/COX-2 activity in some studies, although not the present study, were associated with colorectal cancer risk. Thus, both <i>PTGS2</i> polymorphisms and <i>PTGS2</i> mRNA levels may provide information regarding CRC risk.</p></div