The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis.
Hepatocytes adopt an invasive and metastatic phenotype caused by the cooperation of transforming growth factor (TGF)-beta and oncogenic Ha-Ras. In the initial phase of this process, c-Fos is rapidly induced by TGF-beta, 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.
Mikula
Mario
M
Institute of Cancer Research, University of Vienna, Borschke-Gasse 8a, A-1090 Vienna, Austria.
Gotzmann
Josef
J
Fischer
Alexandra N M
AN
Wolschek
Markus F
MF
Thallinger
Christiane
C
Schulte-Hermann
Rolf
R
Beug
Hartmut
H
Mikulits
Wolfgang
W
D000818:Animals; D017209:Apoptosis; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D016923:Cell Death; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells; D005434:Flow Cytometry; D011905:Genes, ras; D008113:Liver Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016760:Proto-Oncogene Proteins c-fos; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051020:bcl-X Protein; D051742:Transcription Factor CHOP