Regulation of 15-hydroxyprostaglandin dehydrogenase expression in hepatocellular carcinoma
2013
Castro-Sánchez, Luis | Agra, Noelia | Llorente Izquierdo, Cristina | Motiño, Omar | Casado, Marta | Boscá, Lisardo | Martín-Sanz, Paloma
Cyclooxygenase-2 (COX-2), a rate limiting step in arachidonic acid cascade, plays a key role in the biosynthesis of prostaglandin E₂ (PGE₂) upon inflammatory stimuli, growth factors, hormones and other cellular stresses. Overproduction of PGE₂ stimulates proliferation of various cancer cells, confers resistance to apoptosis and favors metastasis and angiogenesis. The steady-state level of PGE₂ is maintained by interplay between the biosynthetic pathway including COX and PGE₂ synthases and the catabolic pathways involving nicotinamide adenine dinucleotide (NAD⁺)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). 15-PGDH is a crucial enzyme responsible for the biological inactivation of PGE₂. Adult hepatocytes fail to induce COX-2 expression regardless of the pro-inflammatory factors used. COX-2 is induced in hepatocytes after partial hepatectomy (PH), in animal models of cirrhosis, in human hepatoma cell lines, in human HCC and after HBV and HCV infection. However, no data are available regarding 15-PGDH expression in HCC. Our results show that 15-PGDH is downregulated in human hepatoma cells with a high COX-2 expression, in chemical and genetic murine models of HCC and in human HCC biopsies. Moreover, 15-PGDH expression is suppressed by EGF (epidermal growth factor) and HGF (hepatocyte growth factor) mainly involving PI3K (phosphatidylinositol-3-kinase), ERK (extracellular signal-regulated kinase) and p38MAPK (mitogen-activated protein kinase) activation. Conversely, ectopic expression of 15-PGDH induces apoptosis in hepatoma cells and decreases the growth of hepatoma cells in nude mice whereas the silencing of 15-PGDH increases the tumor formation. These data suggest a potential therapeutic application of 15-PGDH in HCC.
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