The international journal of biochemistry & cell biology, 2013-11, Vol.45 (11), p.2501-2511
2013
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- Autor(en) / Beteiligte
- Titel
- Regulation of 15-hydroxyprostaglandin dehydrogenase expression in hepatocellular carcinoma
- Ist Teil von
- The international journal of biochemistry & cell biology, 2013-11, Vol.45 (11), p.2501-2511
- Ort / Verlag
- Netherlands: Elsevier Ltd
- Erscheinungsjahr
- 2013
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1357-2725eISSN: 1878-5875DOI: 10.1016/j.biocel.2013.08.005Titel-ID: cdi_proquest_miscellaneous_1671581639
- Format
- –
- Schlagworte
- 15-PGDH, Activation, Adult, adults, angiogenesis, animal models, Animals, Apoptosis, Apoptosis - drug effects, Apoptosis - genetics, arachidonic acid, biochemical pathways, Biopsy, biosynthesis, Carcinoma, Hepatocellular - enzymology, Carcinoma, Hepatocellular - genetics, Carcinoma, Hepatocellular - pathology, Cell Line, Tumor, Cell Proliferation - drug effects, Cell Survival - drug effects, Cell Survival - genetics, Cellular, COX-2, Cyclooxygenase 2 - metabolism, Disease Models, Animal, Down-Regulation - drug effects, Down-Regulation - genetics, Enzymes, epidermal growth factor, Epidermal Growth Factor - pharmacology, gene expression regulation, Gene Expression Regulation, Enzymologic - drug effects, Gene Expression Regulation, Neoplastic - drug effects, Growth factors, HCC, hepatocyte growth factor, Hepatocyte Growth Factor - pharmacology, hepatocytes, hepatoma, Human, Humans, Hydroxyprostaglandin Dehydrogenases - metabolism, Intramolecular Oxidoreductases - metabolism, Kinases, Liver Neoplasms - enzymology, Liver Neoplasms - genetics, Liver Neoplasms - pathology, MAP Kinase Signaling System - drug effects, MAP Kinase Signaling System - genetics, metastasis, Mice, Mice, Inbred C57BL, mitogen-activated protein kinase, NAD (coenzyme), neoplasm cells, Pathways, phosphatidylinositol 3-kinase, Phosphatidylinositol 3-Kinases - metabolism, prostaglandin synthase, Prostaglandin-E Synthases, prostaglandins, Receptor, Epidermal Growth Factor - metabolism, RNA, Messenger - genetics, RNA, Messenger - metabolism, Tumor growth