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Hepatocellular expression of a dominant-negative mutant TGF-β type II receptor accelerates chemically induced hepatocarcinogenesis

Oncogene volume 20, pages 5015–5024 (2001)Cite this article

Abstract

The potent growth-inhibitory activity of cytokines of the transforming growth factor-β (TGF-β) superfamily and their widespread expression in epithelia suggest that they may play an important role in the maintenance of epithelial homeostasis. To analyse TGF-β mediated tumor suppressor activity in the liver, we generated transgenic mice overexpressing a dominant negative type II TGF-β receptor in hepatocytes under control of the regulatory elements of the human C-reactive protein gene promoter. Transgenic animals exhibited constitutive and liver-specific transgene expression. The functional inactivation of the TGF-β signaling pathway in transgenic hepatocytes was shown by reduced TGF-β induced inhibition of DNA synthesis in primary hepatocyte cultures. Liver morphology and spontaneous tumorigenesis were unchanged in transgenic mice suggesting that interruption of the signaling of all three isoforms of TGF-β in hepatocytes does not disturb tissue homeostasis in the liver under physiological conditions. However, following initiation with the carcinogen diethylnitrosamine and tumor-promotion with phenobarbital transgenic mice exhibited a moderate albeit significant increase in the incidence, size and multiplicity of both preneoplastic tissue lesions in the liver and of hepatocellular carcinomas. These results give in vivo evidence for a tumor suppressor activity of the endogeneous TGF-β system in the liver during chemical hepatocarcinogenesis.

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Abbreviations

The abbreviations used are: TGF-β:

transforming growth factor-β

TβRII:

transforming growth factor-β type II receptor

ΔkTβRII:

dominant negative mutant of the TGF-β type II receptor

CRP:

C-reactive protein

HCC:

hepatocellular carcinoma

PBS:

phosphate-buffered saline

DEN:

diethylnitrosamine

PB:

phenobarbital

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Acknowledgements

We thank C Waldmann, D Friebe and K Petmecky for excellent technical assistance. We thank U Ruether (Hannover, Germany) for supplying a cDNA clone of the human CRP promoter. We are endebted to Prof Meyer zum Büschenfelde for constant encouragement and support. We are particularly grateful to Prof Schulte-Hermann for critical reading of the manuscript and helpful comments. This work was funded by the Boehringer Ingelheim Foundation and the Deutsche Krebshilfe.

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  1. Stephan Kanzler and Erik Meyer: S Kanzler and E Meyer contributed equally to the study.

Authors and Affiliations

  1. Department of Medicine, University of Mainz, Mainz, 55131, Germany

    Stephan Kanzler, Erik Meyer, Ansgar Wilhelm Lohse, Jürgen Henninger, Peter Robert Galle & Manfred Blessing

  2. Department of Pathology, University of Cologne, Cologne, 50931, Germany

    Peter Schirmacher

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  1. Stephan Kanzler
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Correspondence to Manfred Blessing.

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Kanzler, S., Meyer, E., Lohse, A. et al. Hepatocellular expression of a dominant-negative mutant TGF-β type II receptor accelerates chemically induced hepatocarcinogenesis. Oncogene 20, 5015–5024 (2001). https://doi.org/10.1038/sj.onc.1204544

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