Carcinogenesis Advance Access originally published online on February 10, 2005
Carcinogenesis 2005 26(5):931-942; doi:10.1093/carcin/bgi043
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Carcinogenesis vol.26 no.5 © Oxford University Press 2005; all rights reserved.
Integration of Ras subeffector signaling in TGF-ß mediated late stage hepatocarcinogenesis
1 Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschke-Gasse 8a, A-1090 Vienna, Austria, 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, Austria and 4 Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, A-1030 Vienna, Austria
* To whom correspondence should be addressed. Tel: +43 1 4277 65250; Fax: +43 1 4277 65239; Email: wolfgang.mikulits{at}meduniwien.ac.at
Immortalized p19ARF null hepatocytes (MIM) feature a high degree of functional differentiation and are susceptible to transforming growth factor (TGF)-ß driven growth arrest and apoptosis. In contrast, polarized MIM hepatocytes expressing hyperactive Ha-Ras continue proliferation in cooperation with TGF-ß, 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-ß mediated hepatocellular EMT by employing MIM hepatocytes, which express Ras mutants allowing selective activation of either mitogen-activated protein kinase (MAPK) signaling (V12-S35) or phosphoinositide 3-OH (PI3)3 kinase (PI3K) signaling (V12-C40). We found that MAPK signaling in MIM-S35 hepatocytes was necessary and sufficient to promote resistance to TGF-ß 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-ß mediated growth arrest. In vivo, the collaboration of MAPK signaling and TGF-ß activity drastically accelerated the cell-cycle progression of the hepatocytes, leading to vast tumor formation. From these data we conclude that MAPK is crucial for the cooperation with TGF-ß to regulate the proliferation as well as the survival of hepatocytes during EMT, and causes the fatal increase in hepatocellular tumor progression.
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