Carcinogenesis Advance Access published online on November 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm236
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Autonomous growth and hepatocarcinogenesis in transgenic mice expressing the p53 family inhibitor deltaNp73
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1 Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock Medical School, Schillingallee 69, D-18055 Rostock, Germany
2 Department of Pathology, Ruhr University, Bürkle-de-la Camp-Platz 1, D-44789 Bochum, Germany
3 Immunogenetics Research Group, University of Rostock Medical School, Schillingallee 70, D-18055 Rostock, Germany
* To whom correspondence should be addressed: Brigitte M. Pützer, University of Rostock, Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, Schillingallee 69, D-18055 Rostock, Germany. Email: brigitte.puetzer{at}med.uni-rostock.de; Tel.: +49 381 494-5066/5068; Fax:+49 381 494-5062
p53 family proteins carry on a wide spectrum of biological functions from differentiation, cell cycle arrest, apoptosis, and chemosensitivity of tumors. Conversely, N-terminally truncated p73 (deltaNp73) functions as a potent inhibitor of all these tumor suppressor properties, implicating its participation in malignant transformation and oncogenesis. Several reports indicated considerable upregulation of deltaNp73 in hepatocellular carcinoma (HCC) that correlates with reduced survival of patients, but little is known about the functional significance of deltaNp73 to tumorigenesis in vivo due to the lack of an appropriate model. To address this, we generated transgenic mice in which deltaNp73 expression is directed to the liver by the albumin promoter. Gene expression was tested by mRNA and protein analyses. Transgenic mice exhibited prominent hepatic histological abnormalities including increased hepatocyte proliferation resulting in preneoplastic lesions (liver cell adenomas) at 3-4 months. Among 12-to-20-months old mice, 83% of animals developed hepatic carcinoma. HCC displayed a significant increase of hyperphosphorylated inactive Rb, whereas p53-regulated inhibitors of cell cycle progression were downregulated in the tumors. Our data firmly establish the unique oncogenic capability of deltaNp73 to drive hepatocarcinogenesis in vivo, supporting its significance as a marker for disease severity in patients and as target for cancer prevention. This model offers new opportunities to further delineate deltaNp73-mediated liver oncogenesis but may also enable the development of more effective cancer therapies.
These authors contributed equally to this work. # Present address: Renal Section, Division of Medicine, Imperial College London, Du Cane Road, London, W12 ONN, UK
Received August 22, 2007; revised October 10, 2007; accepted October 18, 2007.