| Development of gastric cancer is believed to be a multi-step progression from chronic gastritis, glandular atrophy, intestinal metaplasia (IM), dysplasia and ultimately to carcinoma. However, the molecular mechanisms leading to gastric cancer development remain largely unknown. Recently, two mechanisms have been demonstrated to contribute to colorectal carcinogenesis, namely microsatellite instability (MSI) and cyclooxygenase-2 (COX-2) overexpression. MSI, a well-characterized phenotype that implicates underlying defect of DNA mismatch repair, is found to account for a subset of gastric tumors. On the other hand, over-expression of COX-2, an inducible form of prostaglandin synthase, is also frequently detected in gastrointestinal cancer. Intriguingly, tumors with MSI phenotypes or COX-2 overexpression present with contrasting clinicopathological features, which may suggest distinct cancer development pathways and possible differential responses to treatment. These series of experiments sought to elucidate the role of MSI and COX2 in the gastric carcinogenesis process. The results showed that both MSI and COX-2 were frequently detected in premalignant gastric lesions as well as in gastric cancer. Chronic H. pylori infection and p53 mutation play a crucial role in the overexpression of COX-2 in gastric cancer. Nevertheless, eradication of H. pylori alone did not appear to retard the progression of IM despite a modest reduction in COX-2 expression. On the other hand, the two mutL component of the DNA mismatch repair proteins (hPMS1 and hMLH1) interact to form a hetero-dimer in human gastric cells that support the importance of hMLH1 in the stabilization of this complex, and hence the integrity of DNA mismatch repair function. Lastly, gastric cancers with MSI phenotypes had significantly reduced COX-2 expression, which may have significant implications on their response to potential chemopreventive effects of COX-2 inhibitors. These series of experiments broaden the current understanding of the gastric carcinogenesis process and further support the role of intestinal metaplasia in this transformation pathway. |
