title: Transgenic mice expressing cyclooxygenase-2 in hepatocytes reveal a minor contribution of this enzyme to chemical hepatocarcinogenesis.
abstract: Cyclooxygenase-2 (COX-2) has been associated with cell growth regulation, tissue remodeling, and carcinogenesis. Ectopic expression of COX-2 in hepatocytes constitutes a nonphysiological condition ideal for evaluating the role of prostaglandins (PGs) in liver pathogenesis. The effect of COX-2-dependent PGs in chronic liver disease, hepatitis, fibrosis, and chemical hepatocarcinogenesis, has been investigated in transgenic (Tg) mice that express human COX-2 in hepatocytes and in Tg hepatic human cell lines. We have used three different complementary approaches: i) diethylnitrosamine (DEN)-induced chemical hepatocarcinogenesis in COX-2 Tg mice, ii) DEN/phenobarbital treatment of human COX-2 Tg hepatocyte-like cells, and iii) COX-2 Tg hepatocyte-like cells implants in nude mice. The data suggest that PGs produced by COX-2 in hepatocytes promoted mild hepatitis in 60-week-old mice, as assessed by histological examination, but failed to contribute to the development of liver fibrogenesis after methionine- and choline-deficient diet treatment. Moreover, liver injury, collagen content, and hepatic stellate cell activation were equally severe in wild-type and COX-2 Tg mice. The contribution of COX-2-dependent PGs to the development of DEN-induced hepatocarcinogenesis was evaluated in Tg mice, Tg hepatocyte-like cells, and nude mice and the analysis revealed that COX-2 expression favors the development of preneoplastic foci without affecting malignant transformation. Endogenous COX-2 expression in wild-type mice is a late event in the development of hepatocellular carcinoma.
authors.affiliation: Institute of Biomedical Research Alberto Sols (CSIC-UAM), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Llorente Izquierdo
authors.forename: Rafael
authors.initials: R
authors.lastname: Mayoral
authors.forename: Juana María
authors.initials: JM
authors.lastname: Flores
authors.forename: Pilar
authors.initials: P
authors.lastname: García-Palencia
authors.forename: Carme
authors.initials: C
authors.lastname: Cucarella
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.forename: Marta
authors.initials: M
authors.lastname: Casado
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001835:Body Weight; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D019927:Cyclin E / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004052:Diethylnitrosamine; D015972:Gene Expression Regulation, Neoplastic; D006505:Hepatitis / Q000150:complications / Q000473:pathology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009929:Organ Size; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D019927:Cyclin E; D016271:Proto-Oncogene Proteins c-myc; D004052:Diethylnitrosamine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human