15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Gastric Cancer

Abstract

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-1h (IL-1h) 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), the15-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-1h repressed expression of 15-PGDH mRNA and protein. This effect of IL-1h 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-1h, suppresses 15-PGDH expression at least partially by inhibiting promoter activity of the 15-PGDH gene.

Loss of 15-Hydroxyprostaglandin Dehydrogenase Expression Contributes to Bladder Cancer Progression

“…These data are consistent with other reports showing that PGDH acts as a tumor suppressor in breast, colon, lung, and gastric cancers. [11][12][13][14][15] Studies of PGDH expression in bladder cancer are aided by the fact that the urinary bladder is an easily accessible organ, and many tumors in various tumor stages are treated with surgical resection. 27 Thus, studies of bladder cancer allow more detailed evaluation of changes during cancer development.…”

“…10 PGDH expression is reduced in colon, breast, gastric and lung cancers, and restoration can inhibit tumorigenesis in xenografts, thus PGDH is recognized as a tumor suppressor in those cancers. [11][12][13][14][15] Therefore, PGDH is important for regulating cancer development and progression.…”

Postnatal regulation of 15-hydroxyprostaglandin dehydrogenase in the rat kidney

“…This was further supported by the finding that suppression of 15-PGDH expression by 15-PGDH small interfering (si) RNA led to a further increase in the IL-1␤-induced expression of COX-2 (31,33). In another experiment, siRNA knockdown of 15-PGDH resulted in a substantial increase in PGE 2 production in gastric cancer (MKN-28) cells and enhanced the anchorage-independent growth of these cells (32). The expression of COX-2 protein is also responsible for attenuation of 15-PGDH expression.…”

Recovery of Genes Epigenetically Altered by the Histone Deacetylase Inhibitor Scriptaid and Demethylating Agent 5-Azacytidine in Human Leukemia Cells

“…It is inversely correlated with VEGF expression in colorectal cancer (Lim et al, 2010). HPGD is down-regulated in gastric cancer (Thiel et al, 2009). Reduction of HPGD expression is an independent predictor of poor survival, associated with enhanced cell proliferation in gastric adenocarcinoma (Tatsuwaki et al, 2010).…”