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Smad4 induces the tumor suppressor E-cadherin and P-cadherin in colon carcinoma cells

Oncogene volume 21, pages 6049–6058 (2002)Cite this article

Abstract

Smad4 is an intracellular transmitter of TGF-β signals and its tumor suppressor function is presumed to reside in its capacity to mediate TGF-β-induced growth inhibition. However, there is accumulating evidence that this hypothesis may be too simple. The roles of TGF-β in carcinogenesis are complex and also comprise tumor promoting functions particularly in late stage carcinogenesis. Importantly, functional inactivation of Smad4 in colon carcinomas frequently occurs at late stages when tumors acquire invasive and metastatic capabilities. We have previously reported that stable re-expression of Smad4 in SW480 human colon carcinoma cells was adequate to suppress tumor growth in nude mice. However, it did not affect cell growth in vitro nor did it restore TGF-β responsiveness. Here, we report that Smad4 transcriptionally induced classical cadherins including the invasion suppressor E-cadherin, presumably re-establishing epithelial morphology. Smad4-induced cadherins were able to recruit catenins to the plasma membrane and were functionally active in cell–cell adhesion. These results indicate a novel pathway of Smad4-mediated tumor suppression and suggest that Smad4 in colon cells may be involved in the maintenance of epithelial traits.

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Abbreviations

conA:

concanavalin A

DMEM:

Dulbecco's modified Eagle medium

EDTA:

ethylenediaminetetraacetic acid

EGTA:

ethyleneglycoltetraacetic acid

FITC:

fluorescein isothiocyanate

HBSS:

Hank's balanced salt solution

IHC:

immunohistochemistry

PMSF:

phenylmethylsulphonyl fluoride

RPA:

ribonuclease protection assay

TGF-β:

transforming growth factor beta

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Acknowledgements

The authors thank S Landsberg for IHC, C Theiss for assistance with confocal microscopy, D Thomas for RPA analysis and C Niessen for critically reading the manuscript. The polyclonal rabbit antisera against α- and β-catenin were a kind gift of BM Gumbiner (Memorial Sloan-Kettering Cancer Center, NY, USA). This work was supported by grants from the Deutsche Krebshilfe – Dr Mildred Scheel-Stiftung, from the Wilhelm Sander-Stiftung and from the Ruhr-Universität Bochum, FoRUM program (to I Schwarte-Waldhoff, A Reinacher-Schick and W Schmiegel) and by grants from the FWO, the Geconcerteerd Onderzoeksacties of Ghent University, and the Fortis Bank-Verzekeringen, Brussels, Belsium (to F van Roy). J van Hengel and G Berx are postdoctoral fellows with the FWOP (Fund for Scientific Research, Flanders).

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  1. Nicole Müller and Anke Reinacher-Schick: N Müller and A Reinacher-Schick contributed equally to this paper and should be considered as first authors

Authors and Affiliations

  1. Department of Internal Medicine, IMBL, University of Bochum, Bochum, Germany

    Nicole Müller, Anke Reinacher-Schick, Anke Baar, Wolff Schmiegel & Irmgard Schwarte-Waldhoff

  2. Department of Pathology, University of Cologne, Germany

    Stephan Baldus

  3. Department for Molecular Biomedical Research, Molecular Cell Biology Unit, VIB, Ghent University, Ghent, Belgium

    Jolanda van Hengel, Geert Berx & Frans van Roy

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Correspondence to Irmgard Schwarte-Waldhoff.

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Müller, N., Reinacher-Schick, A., Baldus, S. et al. Smad4 induces the tumor suppressor E-cadherin and P-cadherin in colon carcinoma cells. Oncogene 21, 6049–6058 (2002). https://doi.org/10.1038/sj.onc.1205766

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