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DPC4/SMAD4 mediated tumor suppression of colon carcinoma cells is associated with reduced urokinase expression

Oncogene volume 18, pages 3152–3158 (1999)Cite this article

Abstract

We recently identified DPC4/Smad4 as a candidate tumor suppressor gene mutated or lost in one half of pancreatic carcinomas and in a subset of colon and biliary tract carcinomas. DPC4 plays a key role in signal transduction of the TGF-β superfamily of molecules and inactivation of TGF-β mediated growth inhibition is supposed to be the driving force for DPC4 inactivation in human tumors. However, DPC4 mediated tumor suppression by reconstitution of defective cells has not yet been reported. Here we show suppression of tumorigenicity in nude mice by stable reexpression of DPC4 in SW480 colon carcinoma cells. In vitro growth of DPC4-transfected cells was not affected and resistance towards TGF-β mediated growth inhibition was retained. Instead, cells exhibited morphological alterations and adhesion and spreading were accelerated. These phenotypic changes were associated with reduced expression levels of the endogenous urokinase-type plasminogen activator (uPA) and plasminogen-activator-inhibitor-1 (PAI-1) genes, the products of which are implicated in the control of cell adhesion and invasion. In patients, high expression levels of uPA and PAI-1 correlate with poor prognosis. Thus, reduced expression of uPA and PAI-1 is consistent with suppression of tumorigenicity in DPC4 reconstituted cells. These results demonstrate DPC4's tumor suppressive function and suggest a potential role for DPC4 as a modulator of cell adhesion and invasion.

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Acknowledgements

We thank I Neumann and M Becker for expert technical assistance, J Massagué, J Wrana and T Gress for providing plasmids and probes, P Lorenz for help with antibody production and MF Rajewsky for support. We gratefully acknowledge R Schäfer and W Doerfler for critical review of the manuscript. This work was supported by grants from the Dr Mildred Scheel Stiftung für Krebsforschung (10-1137-HaI), from the BMBF (01 KV 9529) and from the Ruhr-Universität Bochum.

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Authors and Affiliations

  1. Medizinische Universitätsklinik, Knappschaftskrankenhaus, Ruhr-Universität Bochum, Bochum, D44892, Germany

    Irmgard Schwarte-Waldhoff, Susanne Klein, Annette Hintelmann, Christina Eilert, Stephan Dreschers, Stephan A Hahn & Wolff Schmiegel

  2. Institut für Zellbiologie (Tumorforschung), Universitätsklinik Essen, Essen, D45122, Germany

    Sabine Blass-Kampmann

  3. Klinik für Allgemeine und Thoraxchirurgie, CAU Kiel, Kiel, D24105, Germany

    Holger Kalthoff

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  1. Irmgard Schwarte-Waldhoff
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Schwarte-Waldhoff, I., Klein, S., Blass-Kampmann, S. et al. DPC4/SMAD4 mediated tumor suppression of colon carcinoma cells is associated with reduced urokinase expression. Oncogene 18, 3152–3158 (1999). https://doi.org/10.1038/sj.onc.1202641

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