An integrative model on the role of DMBT1 in epithelial cancer

J Mollenhauer, PhDa, B Helmke, MDb, H Müller, MDa, G Kollendera, I Krebs, PhDa, S Wiemann, PhDa, U Holmskov, PhDc, J Madsenc, HF Otto, PhDb, A Poustka, PhDa

a Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany; b University Heidelberg, 69120 Heidelberg, Germany; c University of Southern Denmark, DK-5000 Odense-C, Denmark.

AIMS: The gene Deleted in Malignant Brain Tumors 1 (DMBT1) at chromosome 10q25.3-q26.1 has been proposed as a candidate tumor suppressor gene for brain and epithelial cancer. We aimed at gaining initial insights in the mechanisms by which DMBT1 may contribute to tumorigenesis. METHODS: We characterized genomic alterations of DMBT1 in tumors of different origin by Southern blot and single strand conformation polymorphism analyses and its expression in normal tissues and cancer by immunohistochemistry. Furthermore, transcripts from different sources were isolated and analyzed. RESULTS: One half of the genomic alterations in brain and lung cancer comprises variable numbers of tandem repeats also prevalent in the normal population. The other half represents presumable mutations acquired during tumorigenesis. Any of the alterations affects the exons coding for the scavenger receptor cysteine-rich domains and the small interspersed domains. In contrast, the genomic integrity is maintained in melanomas arguing against a random instability of the gene. The basic characterization of DMBT1 indicates that it is related to mucins. DMBT1 is secreted to the extracellular matrix (ECM) in human adult multilayered epithelia and is down-regulated at early stages of squamous cell carcinomas. In contrast, DMBT1 is secreted to the lumen by human adult monolayered epithelia and upregulated in response to tumors and upon inflammation. In carcinomas originating from monolayered epithelia, DMBT1 is down-regulated at later stages after an aberrant secretion to the ECM has taken place. CONCLUSIONS: The results give rise to a model on the role of DMBT1 in epithelial cancer, which suggests that both, its functions in protection and differentiation are of potential importance for the prevention of carcinogenesis.

KEY WORDS: Genomic instability, Mucin, Mucosal protection, Epithelial differentiation.

For more information, contact

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prevention.