15-hydroxyprostaglandin dehydrogenase is down-regulated in gastric cancer.

Purpose: We have investigated the expression and regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in gastric cancer. Experimental Design: Clinical gastric adenocarcinoma samples were analyzed by immunohistochemistry and quantitative real-time PCR for protein and mRNA expression of 15-PGDH and for methylation status of 15-PGDH promoter. The effects of interleukin-1β (IL-1β) and epigenetic mechanisms on 15-PGDH regulation were assessed in gastric cancer cell lines. Results: In a gastric cancer cell line with a very low 15-PGDH expression (TMK-1), the 15-PGDH promoter was methylated and treatment with a demethylating agent 5-aza-2′-deoxycytidine restored 15-PGDH expression. In a cell line with a relatively high basal level of 15-PGDH (MKN-28), IL-1β repressed expression of 15-PGDH mRNA and protein. This effect of IL-1β was at least in part attributed to inhibition of 15-PGDH promoter activity. SiRNA-mediated knockdown of 15-PGDH resulted in strong increase of prostaglandin E 2 production in MKN-28 cells and increased cell growth of these cells by 31% in anchorage-independent conditions. In clinical gastric adenocarcinoma specimens, 15-PGDH mRNA levels were 5-fold lower in gastric cancer samples when compared with paired nonneoplastic tissues ( n = 26) and 15-PGDH protein was lost in 65% of gastric adenocarcinomas ( n = 210). Conclusions: 15-PGDH is down-regulated in gastric cancer, which could potentially lead to accelerated tumor progression. Importantly, our data indicate that a proinflammatory cytokine linked to gastric carcinogenesis, IL-1β, suppresses 15-PGDH expression at least partially by inhibiting promoter activity of the 15-PGDH gene.