Analysis of specific transcriptional regulators as early predictors of independent prognostic relevance in resected colorectal cancer
Analysis of specific transcriptional regulators as early predictors of independent prognostic relevance in resected colorectal cancer
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DOI：
10.1158/1078-0432.ccr-06-1668
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发表时间：
2007-02-15
影响因子：
11.5
通讯作者：
Allgayer, Heike
中科院分区：
文献类型：
--
作者：
Maurer, Gabriele D.;Leupold, Joerg H.;Allgayer, Heike
目的：迄今为止，尚未对作用于特定启动子元件的转录因子进行预后研究。然而，对于需要长时间随访的肿瘤，如结肠直肠癌，早期风险预测是必要的。入侵相关基因u-PAR通过激活蛋白2 (AP-2)/Sp1（-152/-135）和AP-1结合启动子基序（-190/ -171）调控，介导K-Ras和Src对u-PAR的诱导。本研究旨在为结直肠癌中与u-PAR启动子差异结合的转录因子及其分子诱导剂的早期预后相关性提供第一个证据。实验设计：对92例前瞻性随访（中位数= 26.3个月）患者的肿瘤/正常组织进行Src活性/蛋白、K-ras突变和转录因子结合u-PAR启动子基序（体内凝胶转移、激酶测定和PCR）的分析。结果：Kaplan-Meier/Mantel-Cox分析显示，Sp1/Sp3结合-152/-135区升高（P = 0.002和P = 0.006）， Sp1/ AP-2和Sp1/AP-1结合两个基元的组合（P = 0.010和P = 0.005）， Sp1结合/高Src蛋白在肿瘤中存在显著相关性（P < 0.001），生存率较差。生存率随着与两个基序结合的转录因子数量的减少而降低，其中三个因子的结合定义了高风险群体（P = 0.021）。在多变量分析中，Sp1结合升高，Sp1/AP-2结合和Sp1/AP-1结合的组合，或Sp1结合/高Src是独立的预后变量；u-PAR表达本身还不能预测预后。定义了第一个分子分期模型（CART），从这些变量中提供了新的早期高危组（平均生存时间与非治愈性切除患者一样低）。结论：本研究确定了转录因子作用于侵袭相关基因的特定启动子元件，介导特定信号传导，作为结直肠癌预后的新的、独立的早期预测因子。
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.