1. ¹Department of Internal Medicine, Knappschaftskrankenhaus, IMBL, Ruhr-University of Bochum, Bochum, Germany
2. ²INSERM U682, Development and Physiopathology of the Intestine and Pancreas, University Louis Pasteur, Strasbourg, France
3. ³Institute of Pathology, BG Kliniken Bergmannsheil, University of Bochum, Bochum, Germany
4. ⁴Department of Internal Medicine, Knappschaftskrankenhaus, University of Bochum, Bochum, Germany
5. ⁵Department of Gastroenterology and Hepatology, Kliniken Bergmannsheil, University of Bochum, Bochum, Germany

Correspondence: Dr I Schwarte-Waldhoff, Department of Internal Medicine, Knappschaftskrankenhaus, IMBL, Ruhr-University Bochum, In der Schornau 23-25, Bochum D 44892, Germany. E-mail: Irmgard.Schwarte-Waldhoff@ruhr-uni-bochum.de

⁶Current address: Department of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.

⁷These authors contributed equally to this work.

Received 28 February 2006; Revised 13 July 2006; Accepted 18 July 2006; Published online 4 September 2006.

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- (TGF-) superfamily of cytokines. Despite extensive knowledge about the mechanisms of TGF-/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.