15-Prostaglandin Dehydrogenase Inhibition Enhances Colon Cancer Metastasis by Up- regulation of Epithelial-to-Mesenchymal Transition Genes

Background/Aim: Most deaths from colon cancer are due to metastasis. Recently, PGE2 was found to influence colon cancer invasion and metastasis. 15-PGDH, an enzyme that metabolizes PGE2, is known as a tumor suppressor in colonic carcinogenesis. This study investigated the effect of 15-PGDH on colon cancer metastasis. Materials and Methods: 15-PGDH expression by immunohistochemical staining, clinicopathologic features, and 5- year cancerspecific survival were investigated in colon cancer patients. Liver metastasis was examined by assaying 15-PGDH activity in an animal model. Changes in PGE2, proliferation, migration, and invasion of the colorectal cancer cell line HCT116, were examined using a 15- PGDH inhibitor (SW033291) or enhancer (CDDO-ME). The expression of genes involved in the epithelial- to- mesenchymal transition (EMT) was also studied. Results: The absence of 15-PGDH expression significantly correlated with advanced-stage, lymph node metastasis, and decreased cancer-specific survival in colon cancer patients. Inhibition of 15-PGDH increased colon cancer liver metastasis in the animal model. The 15-PGDH inhibitor, SW033291, increased PGE2 and decreased 15-PGDH expression on HCT116. However, treatment with CDDO-ME, a substance that enhances 15PGDH, showed the opposite results. Inhibition of 15- PGDH increased cell proliferation, migration, and invasion, but activation of 15-PGDH showed the opposite effect. Inhibition of 15-PGDH also affected the EMT markers, N- cadherin, Snail, and Twist2. Conclusion: 15-PGDH inhibition increased colon cancer metastasis by inducing changes in EMT-related genes via an increase in PGE2 expression and could be a promising biomarker for anticancer treatment.