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A crucial function of PDGF in TGF-β-mediated cancer progression of hepatocytes

Oncogene volume 25, pages 3170–3185 (2006)Cite this article

Abstract

Polarized hepatocytes expressing hyperactive Ha-Ras adopt an invasive and metastatic phenotype in cooperation with transforming growth factor (TGF)-β. This dramatic increase in malignancy is displayed by an epithelial to mesenchymal transition (EMT), which mimics the TGF-β-mediated progression of human hepatocellular carcinomas. In culture, hepatocellular EMT occurs highly synchronously, facilitating the analysis of molecular events underlying the various stages of this process. Here, we show that in response to TGF-β, phosphorylated Smads rapidly translocated into the nucleus and activated transcription of target genes such as E-cadherin repressors of the Snail superfamily, causing loss of cell adhesion. Within the TGF-β superfamily of cytokines, TGF-β1, -β2 and -β3 were specific for the induction of hepatocellular EMT. Expression profiling of EMT kinetics revealed 78 up- and 235 downregulated genes, which preferentially modulate metabolic activities, extracellular matrix composition, transcriptional activities and cell survival. Independent of the genetic background, platelet-derived growth factor (PDGF)-A ligand and both PDGF receptor subunits were highly elevated, together with autocrine secretion of bioactive PDGF. Interference with PDGF signalling by employing hepatocytes expressing the dominant-negative PDGF-α receptor revealed decreased TGF-β-induced migration in vitro and efficient suppression of tumour growth in vivo. In conclusion, these results provide evidence for a crucial role of PDGF in TGF-β-mediated tumour progression of hepatocytes and suggest PDGF as a target for therapeutic intervention in liver cancer.

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Acknowledgements

We thank Dr Marco Tripodi for MMH-D3 cells, Dr Peter ten Dijke for antibodies against Smads and the BMP-specific reporter construct, Dr Carol Hill for Smad2- and Smad3-dependent reporter constructs, Dr Hyeong-Reh Choi Kim for the vector encoding the dnPDGF-α receptor and Dr Hardy Loeber for FDCP cells. We are further deeply grateful to Dr Peter Seither, Werner Rust and Dr Norbert Kraut for their strong assistance in microarray analysis. This work was supported by Grants ‘HSJ2’ from the Hochschuljubiläumsstiftung der Stadt Wien to JG and from the ‘Jubiläumsfonds der Oesterreichischen Nationalbank’, OENB 10171, and by the ‘Fonds zur Förderung der wissenschaftlichen Forschung’, FWF P15435, Austria to WM.

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  1. J Gotzmann

    Present address: Max F Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Medical Biochemistry, Medical University of Vienna, Vienna, Austria

  2. J Gotzmann, A N M Fischer and M Zojer: 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

    J Gotzmann, A N M Fischer, M Zojer, M Mikula, V Proell, H Huber & W Mikulits

  2. Research Institute of Molecular Pathology, Vienna, Austria

    M Jechlinger, T Waerner & H Beug

  3. Boehringer Ingelheim Pharma KG, Genomics Group, Biberach, Germany

    A Weith

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Gotzmann, J., Fischer, A., Zojer, M. et al. A crucial function of PDGF in TGF-β-mediated cancer progression of hepatocytes. Oncogene 25, 3170–3185 (2006). https://doi.org/10.1038/sj.onc.1209083

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