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Tumor-specific Transcription Factor Binding to an Activator Protein-2/Sp1 Element of the Urokinase-type Plasminogen Activator Receptor Promoter in a First Large Series of Resected Gastrointestinal Cancers¹

Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians University of Munich, 81377 Munich, Germany [D. M. S., J. H. L., K. U. G., F. W. S., K. W. J., H. A.]; Department of Cancer Biology, M. D. Anderson Cancer Center, Houston, Texas 77030 [D. D. B., H. W.]; and Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, Comprehensive Cancer Center and CancerResearch Institute, San Francisco, California [E. R. L.]

Purpose: Evidence for transactivation of genes via specific promoter elements has been derived from studies on tumor cell lines but rarely on resected tumors. However, the proof of an in vivo relevance and the identification of patients with a potential tumor-specific gene expression is essential to transfer molecular-targeting strategies into clinical applications. This study gives the first clinical evidence that urokinase-type plasminogen activator receptor (u-PAR) gene expression is tumor-specifically regulated via an activator protein (AP)-2/Sp1 promoter element in a large patient subpopulation.

Experimental Design: In 145 gastrointestinal cancer patients, electrophoretic mobility shift analysis and supershift assays for u-PAR-promoter region -152/-135 were performed in tumors and corresponding normal tissues. u-PAR protein levels were measured by ELISA.

Results: Binding of Sp1 to region -152/-135 in tumors in contrast to corresponding normal mucosae was observed in 55% of colorectal and in 52% of gastric cancer patients. Tumor-specific binding of an AP-2-related factor was seen in 59% of colorectal and in 63% of gastric cancer patients. A significant correlation between AP-2 (P < 0.0001) and Sp1 (P = 0.0003) binding with a high u-PAR expression was observed in tumors but not in normal mucosae. Tissues of five nontumor patients did not show transcription factor binding to this region.

Conclusions: This is the first study to show the tumor-specific binding of trans-activators to the u-PAR promoter region (-152/-135) biochemically in a large series of resected tumors. For the subpopulation of 60% of patients with tumor-restricted u-PAR-transactivation, a molecular targeting of this region or its activating pathways should be pursued as a new antimetastasis therapy approach.

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