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Transgenic mice expressing cyclooxygenase-2 in hepatocytes reveal a minor contribution of this enzyme to chemical hepatocarcinogenesis

AuthorsLlorente-Izquierdo, Cristina CSIC; Mayoral, Rafael CSIC; Flores, Juana María; García-Palencia, Pilar; Cucarella, Carme CSIC ; Boscá, Lisardo CSIC ORCID CVN; Casado, Marta CSIC ORCID ; Martín-Sanz, Paloma CSIC ORCID
Issue Date2011
PublisherAmerican Society for Investigative Pathology
CitationAmerican Journal of Pathology 178(3): 1361-1373 (2011)
AbstractCyclooxygenase-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 methionineand 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. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Publisher version (URL)http://dx.doi.org/10.1016/j.ajpath.2010.11.074
Identifiersdoi: 10.1016/j.ajpath.2010.11.074
issn: 0002-9440
e-issn: 1525-2191
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