Analysis of specific transcriptional regulators as early predictors of independent prognostic relevance in resected colorectal cancer.
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.
Maurer
Gabriele D
GD
Department of Experimental Surgery and Molecular Oncology of Solid Tumors (German Cancer Research Center), Mannheim Faculty University Heidelberg, Germany.
Leupold
Joerg H
JH
Schewe
Denis M
DM
Biller
Tobias
T
Kates
Ronald E
RE
Hornung
Hans-Martin
HM
Lau-Werner
Ulla
U
Post
Stefan
S
Allgayer
Heike
H
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
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