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Carcinogenesis Advance Access published online on February 10, 2005
Carcinogenesis, doi:10.1093/carcin/bgi043
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received November 24, 2004
Revised January 27, 2005
Accepted February 1, 2005

CANCER BIOLOGY

Integration of Ras subeffector signaling in TGF-{beta} mediated late stage hepatocarcinogenesis

Alexandra N. M. Fischer 1, Blanca Herrera 2, Mario Mikula 1, Verena Proell 1, Eva Fuchs 1, Josef Gotzmann 3, Rolf Schulte-Hermann 1, Hartmut Beug 4, and Wolfgang Mikulits 1*

1 Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschke-Gasse 8a, A-1090 Vienna
2 Department of Biochemistry and Molecular Biology I, Facultad de Ciencias Biológicas, Universidad Complutense de Madrid, Avda/Complutense s/n, 28040 Madrid, Spain
3 Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Medical Biochemistry, Medical University of Vienna, Dr. Bohr-Gasse 9, A-1030 Vienna
4 Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria

* To whom correspondence should be addressed.
Wolfgang Mikulits, E-mail: wolfgang.mikulits{at}meduniwien.ac.at


  Abstract

Immortalized p19ARF null hepatocytes (MIM) feature a high degree of functional differentiation and are susceptible to transforming growth factor (TGF)-{beta} driven growth arrest and apoptosis. In contrast, polarized MIM hepatocytes expressing hyperactive Ha-Ras continue proliferation in cooperation with TGF-{beta}, and adopt an invasive phenotype by executing an epithelial to mesenchymal transition (EMT). In this study, we analyzed the involvement of Ras subeffectors in TGF-{beta} mediated hepatocellular EMT by employing MIM hepatocytes, which express Ras mutants allowing selective activation of either MAPK (V12-S35) or PI3K signaling (V12-C40). We found that MAPK signaling in MIM-S35 hepatocytes was necessary and sufficient to promote resistance to TGF-{beta} mediated inhibition of proliferation in vitro and in vivo. MIM-S35 hepatocytes showed also PI3K activation during EMT, however, MAPK signaling on its own protected hepatocytes from apoptosis. Yet, MIM-C40 hepatocytes failed to form tumors and required additional MAPK stimulation to overcome TGF-{beta} mediated growth arrest. In vivo, the collaboration of MAPK signaling and TGF-{beta} activity drastically accelerated cell cycle progression of hepatocytes, leading to vast tumor formation. From these data we conclude that MAPK is crucial for the cooperation with TGF-{beta} to positively regulate proliferation as well as cell survival of hepatocytes during EMT, and causes the fatal increase in hepatocellular tumor progression.

Keywords: hepatocytes; Ras; PI3K; Erk/MAPK; TGF-{beta}.
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