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PDGF essentially links TGF-β signaling to nuclear β-catenin accumulation in hepatocellular carcinoma progression

Oncogene volume 26, pages 3395–3405 (2007)Cite this article

Abstract

The cooperation of Ras – extracellular signal-regulated kinase/mitogen-activated protein kinase and transforming growth factor (TGF)-β signaling provokes an epithelial to mesenchymal transition (EMT) of differentiated p19ARF null hepatocytes, which is accompanied by a shift in malignancy and gain of metastatic properties. Upon EMT, TGF-β induces the secretion and autocrine regulation of platelet-derived growth factor (PDGF) by upregulation of PDGF-A and both PDGF receptors. Here, we demonstrate by loss-of-function analyses that PDGF provides adhesive and migratory properties in vitro as well as proliferative stimuli during tumor formation. PDGF signaling resulted in the activation of phosphatidylinositol-3 kinase, and furthermore associated with nuclear β-catenin accumulation upon EMT. Hepatocytes expressing constitutively active β-catenin or its negative regulator Axin were employed to study the impact of nuclear β-catenin. Unexpectedly, active β-catenin failed to accelerate proliferation during tumor formation, but in contrast, correlated with growth arrest. Nuclear localization of β-catenin was accompanied by strong expression of the Cdk inhibitor p16INK4A and the concomitant induction of the β-catenin target genes cyclin D1 and c-myc. In addition, active β-catenin revealed protection of malignant hepatocytes against anoikis, which provides a prerequisite for the dissemination of carcinoma. From these data, we conclude that TGF-β acts tumor progressive by induction of PDGF signaling and subsequent activation of β-catenin, which endows a subpopulation of neoplastic hepatocytes with features of cancer stem cells.

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Acknowledgements

We thank Frank Costantini and Tannishtha Reya for providing the Axin construct and the constitutively active β-catenin construct for retroviral transmission, respectively. This work was supported by the Austrian Science Fund (FWF, SFB F28) and by the ‘Jubiläumsfonds der Oesterreichischen Nationalbank’, OENB 10171, Austria.

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  1. A N M Fischer, E Fuchs and M Mikula: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria

    A N M Fischer, E Fuchs, M Mikula, H Huber & W Mikulits

  2. Research Institute of Molecular Pathology, Vienna, Austria

    H Beug

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  1. A N M Fischer
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Correspondence to W Mikulits.

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Fischer, A., Fuchs, E., Mikula, M. et al. PDGF essentially links TGF-β signaling to nuclear β-catenin accumulation in hepatocellular carcinoma progression. Oncogene 26, 3395–3405 (2007). https://doi.org/10.1038/sj.onc.1210121

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