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Basement membrane component laminin-5 is a target of the tumor suppressor Smad4

Oncogene volume 26, pages 1417–1427 (2007)Cite this article

Abstract

The tumor suppressor Smad4 is involved in carcinogenesis mainly of the pancreas and colon. Functional inactivation of Smad4 is a genetically late event that occurs upon transition from premalignant stages to invasive and metastatic growth. Smad4 encodes an intracellular messenger common to all signalling cascades induced by members of the transforming growth factor-β (TGF-β) superfamily of cytokines. Despite extensive knowledge about the mechanisms of TGF-β/Smad signal transduction, little is known about Smad4 targets involved in the transition to malignancy. The hallmark of invasive growth is a breakdown of the basement membrane (BM), a specialized sheet of extracellular matrix produced through cooperation of epithelial and stromal cells. Laminin-5, a heterotrimeric epithelial-derived BM component, is commonly lost in carcinomas but not in premalignant tumors. Herein, we report that in human colon and pancreatic tumor cells, Smad4 functions as a positive transcriptional regulator of all three genes encoding laminin-5. Coordinate re-expression of the three laminin-5 chains induced by reconstitution of Smad4 leads to secretion and deposition of the heterotrimeric molecule in BM-like structures. These data define the expression control of an essential BM component as a novel function for the tumor suppressor Smad4.

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Acknowledgements

We thank H Kalthoff and H Ungefroren for providing recombinant retrovirus, B Marian for providing LT97 cells, F Kanai for providing the Smad4 knockdown vector pcPUR+U6-Smad4i, A Menssen and H Hermeking for introduction in the ChIP assay technology, S Hahn for sequencing and S Klein-Scory and K Schulmann for critically reading the manuscript. This work was supported by grants from the Deutsche Krebshilfe – Dr Mildred Scheel-Stiftung (10-1804-Schw I) and the Wilhelm Sander-Stiftung (99.101.1) to IS-W and WS, by the FoRUM program of the Ruhr-University of Bochum and by Inserm and a grant from the Canceropôle Grand Est to PSA.

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Author notes

  1. M Zapatka

    Present address: Department of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany

  2. M Zapatka and D Zboralski: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Knappschaftskrankenhaus, IMBL, Ruhr-University of Bochum, Bochum, Germany

    M Zapatka, D Zboralski, Y Radacz, M Böckmann, A Schöneck, S Hoppe & I Schwarte-Waldhoff

  2. INSERM U682, Development and Physiopathology of the Intestine and Pancreas, University Louis Pasteur, Strasbourg, France

    C Arnold & P Simon-Assmann

  3. Institute of Pathology, BG Kliniken Bergmannsheil, University of Bochum, Bochum, Germany

    A Tannapfel

  4. Department of Internal Medicine, Knappschaftskrankenhaus, University of Bochum, Bochum, Germany

    W Schmiegel

  5. Department of Gastroenterology and Hepatology, Kliniken Bergmannsheil, University of Bochum, Bochum, Germany

    W Schmiegel

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Correspondence to I Schwarte-Waldhoff.

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Zapatka, M., Zboralski, D., Radacz, Y. et al. Basement membrane component laminin-5 is a target of the tumor suppressor Smad4. Oncogene 26, 1417–1427 (2007). https://doi.org/10.1038/sj.onc.1209918

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  • DOI: https://doi.org/10.1038/sj.onc.1209918

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