title: Analysis of specific transcriptional regulators as early predictors of independent prognostic relevance in resected colorectal cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Experimental Surgery and Molecular Oncology of Solid Tumors (German Cancer Research Center), Mannheim Faculty University Heidelberg, Germany.
authors.forename: Gabriele D
authors.initials: GD
authors.lastname: Maurer
authors.forename: Joerg H
authors.initials: JH
authors.lastname: Leupold
authors.forename: Denis M
authors.initials: DM
authors.lastname: Schewe
authors.forename: Tobias
authors.initials: T
authors.lastname: Biller
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Kates
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Hornung
authors.forename: Ulla
authors.initials: U
authors.lastname: Lau-Werner
authors.forename: Stefan
authors.initials: S
authors.lastname: Post
authors.forename: Heike
authors.initials: H
authors.lastname: Allgayer
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D005260:Female; D011905:Genes, ras; D016391:Genes, src; D006801:Humans; D008297:Male; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D019061:src-Family Kinases