Journal Article

Integration of Ras subeffector signaling in TGF-β mediated late stage hepatocarcinogenesis

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

in Carcinogenesis

Volume 26, issue 5, pages 931-942
Published in print May 2005 | ISSN: 0143-3334
Published online February 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi043
Integration of Ras subeffector signaling in TGF-β mediated late stage hepatocarcinogenesis

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Immortalized p19ARF null hepatocytes (MIM) feature a high degree of functional differentiation and are susceptible to transforming growth factor (TGF)-β driven growth arrest and apoptosis. In contrast, polarized MIM hepatocytes expressing hyperactive Ha-Ras continue proliferation in cooperation with TGF-β, 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-β 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-β 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-β mediated growth arrest. In vivo, the collaboration of MAPK signaling and TGF-β 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-β to regulate the proliferation as well as the survival of hepatocytes during EMT, and causes the fatal increase in hepatocellular tumor progression.

Keywords: EMT, epithelial to mesenchymal transition; GFP, green fluorescent protein; GSK, glycogen synthase kinase; HCC, hepatocellular carcinoma; IGF-II, insulin-like growth factor II; JNK, c-Jun N-terminal kinase; LDH, lactate dehydrogenase; MAPK, mitogen-activated protein kinase; PBS, phosphate-buffered saline; PI3K, phosphoinositide 3-OH (PI3)3 kinase; TGF, transforming growth factor

Journal Article.  8881 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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