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  • Original Paper
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The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis

Oncogene volume 22, pages 6725–6738 (2003)Cite this article

Abstract

Hepatocytes adopt an invasive and metastatic phenotype caused by the cooperation of transforming growth factor (TGF)-β and oncogenic Ha-Ras. In the initial phase of this process, c-Fos is rapidly induced by TGF-β, but then decreases to undetectable levels. Here, we investigated the functional implications of c-Fos activation and its contribution to hepatocellular tumorigenesis. By employing conditional c-Fos expression, we observed that continuous activation of c-Fos and consequently AP-1 activity leads to depolarization of differentiated murine epithelial hepatocytes. Most remarkably, this change in morphology was associated with inhibition of proliferation and induction of cell death. Coexpression of antiapoptotic Bcl-XL or scavenging of reactive oxygen species was sufficient to prevent the c-Fos-mediated phenotype. In contrast, the cooperation of c-Fos with oncogenic Ha-Ras or a Ras mutant selectively activating the MAPK pathway even enhanced c-Fos-induced effects. Showing the negative role in hepatocellular tumorigenesis, c-Fos repressed oncogenic Ras-driven anchorage-independent growth in vitro and strongly suppressed tumour formation in vivo. Taken together, we demonstrate that c-Fos modulates plasticity of epithelial hepatocytes and acts tumour suppressive in neoplastic hepatocytes by stimulating cell cycle inhibition and cell death.

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Acknowledgements

We appreciate Dr Marco Tripodi, Universita La Sapienza, Italy, for providing MMH-D3 cells, Dr Wilhelm Mosgöller for scientific support in histological analyses and Dr Martin Schreiber for helpful discussions and critically reading the manuscript. This work was supported by grants from the ‘Fonds zur Förderung der wissenschaftlichen Forschung’, FWF P15435 and by the ‘Herzfeldersche Family Foundation’, Austria.

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Authors and Affiliations

  1. Institute of Cancer Research, University of Vienna, Borschke-Gasse 8a, Vienna, A-1090, Austria

    Mario Mikula, Josef Gotzmann, Alexandra N M Fischer, Rolf Schulte-Hermann & Wolfgang Mikulits

  2. Department of Clinical Pharmacology, Section of Experimental Oncology, Vienna General Hospital, Währinger Gürtel 18-20, Vienna, A-1090, Austria

    Markus F Wolschek & Christiane Thallinger

  3. Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, Vienna, A-1030, Austria

    Hartmut Beug

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Correspondence to Wolfgang Mikulits.

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Mikula, M., Gotzmann, J., Fischer, A. et al. The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis. Oncogene 22, 6725–6738 (2003). https://doi.org/10.1038/sj.onc.1206781

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