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Analysis of Specific Transcriptional Regulators as Early Predictors of Independent Prognostic Relevance in Resected Colorectal Cancer

Authors' Affiliations: ¹ Department of Experimental Surgery and Molecular Oncology of Solid Tumors (German Cancer Research Center), Mannheim Faculty University Heidelberg; ² Department Surgery Mannheim, University of Heidelberg, Germany; ³ Department of Pediatrics, Dr. v. Haunersches Kinderspital; ⁴ Klinikum Grosshadern, Ludwig Maximilians University; and ⁵ Technical University Munich, Munich, Germany

Requests for reprints: Heike Allgayer, Department Experimental Surgery and Molecular Oncology of Solid Tumors, German Cancer Research Center Heidelberg, Mannheim Faculty, Ruprecht-Karls-Universität Heidelberg, Theodor Kutzer Ufer 1-3, 68135 Mannheim, Germany. Phone: 49-621-383-2226; Fax: 49-621-383-3839; E-mail: heike.allgayer{at}chir.ma.uni-heidelberg.de.

Purpose: Prognostic studies on transcription factors acting at specific promoter elements have never been done so far. However, in tumors with long necessary follow-up, such as colorectal cancer, early-risk predictors would be needed. The invasion-related gene u-PAR is regulated via an activator protein 2 (AP-2)/Sp1 (–152/–135) and an AP-1 binding promoter motif (–190/–171), mediating u-PAR induction by K-Ras and Src. The present study was done to give first evidence for early prognostic relevance of transcription factors differentially bound to the u-PAR promoter, and their molecular inducers, in colorectal cancer.

Experimental Design: Tumor/normal tissues of 92 prospectively followed (median = 26.3 months) patients were analyzed for Src activity/protein, K-ras mutations, and transcription factor binding to both u-PAR promoter motifs (in vivo gel shift, kinase assay, and PCR).

Results: Kaplan-Meier/Mantel-Cox analysis showed a significant correlation among elevated Sp1/Sp3 binding to region –152/–135 (P = 0.002 and P = 0.006), the combinations of Sp1/AP-2 and Sp1/AP-1 binding to both motifs (P = 0.010 and P = 0.005), and Sp1 binding/high Src protein in tumors (P < 0.001), with poor survival. Survival decreased with the number of bound transcription factors to both motifs, with binding of three factors defining a high-risk group (P = 0.021). In multivariate analysis, elevated Sp1 binding, combinations of Sp1/AP-2 binding and Sp1/AP-1 binding, or Sp1 binding/high Src were independent prognostic variables; u-PAR expression itself being not yet prognostic. A first molecular staging model (CART) was defined, providing novel early high-risk groups (mean survival time as low as for non-curatively resected patients) from these variables.

Conclusions: This study defines transcription factors acting at specific promoter elements of an invasion-related gene, mediating specific signaling, as novel, independent, early predictors of prognosis in colorectal cancer.

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