5-hydroxyprostaglandin dehydrogenase expression is downregulated in hepatocellular carcinoma: role in tumor growth

Abstract

[Background and Aims]: 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a tumor suppressor in some cancers. However, no data are available regarding 15-PGDH expression in hepatocellular carcinoma (HCC). We aimed to assess the potential role of 15-PGDH in HCC. [Materials and Methods]: HCC cells lines were treated with EGF, HGF or different pharmacological inhibitors and vehicle as control. COX-2, mPGES-1 and 15-PGDH expression were analyzed by qPCR and Western-blot. Additionally, we induced 15-PGDH overexpression or silencing in a hepatoma cell line, to test in vitro cell viability, cell cycle and apoptosis markers, so as to assess tumor growth in vivo in athymic nu/nu mice. Furthermore, this study comprised a chemical model of liver cancer induced with diethylnitrosamine, a mouse model of accelerated hepatocarcinogenesis and human HCC biopsies where 15-PGDH expression was evaluated. [Results]: 15-PGDH was downregulated in human hepatoma cells with a high COX-2 and mPGES-1 expression. Moreover, EGF and HGF increased COX-2 and mPGES-1 levels and suppressed 15-PGDH expression by mainly involving ERK and p38MAPK activation. Besides, 15-PGDH expression was decreased in chemical and genetic murine models of HCC and in human HCC biopsies. Conversely, ectopic expression of 15-PGDH induced apoptosis in hepatoma cells and decreased the growth of hepatoma cells in nude mice whereas the silencing of 15-PGDH increased the tumor formation by promote increased in cell viability and Sphase cells. [Conclusion]: 15-PGDH expression is downregulated in HCC while the overexpression leads to apoptosis and may function as a relevant tumor suppressor and a potential therapeutic application in HCC.