Mutations in the Ras-Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer
Mutations in the Ras-Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer
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DOI：
10.1158/1078-0432.ccr-11-3066
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发表时间：
2012-06-01
影响因子：
11.5
通讯作者：
Medema, Jan Paul
中科院分区：
文献类型：
--
作者：
Kemper, Kristel;Versloot, Miranda;Medema, Jan Paul
目的：肿瘤干细胞(CSC)标志物CD133的高表达可作为预测结直肠癌(CRC)预后的指标，提示CD133计数CSC可预测疾病进展。然而，我们最近发现，CD133的mRNA和蛋白在结肠癌的分化过程中并没有下调，这表明CD133具有预后价值的另一个原因。因此，我们着手描述CD133的表达与预后的关系。实验设计：通过基因芯片和定量PCR分析，对一组结直肠癌患者的CD133和其他CSC标志物的表达进行研究。结果：CD133基因表达可预测患者无复发生存期，而其他几种CSC标志物不能预测无复发生存期。此外，未发现其他CSC标志物的表达与CD133的相关性。有趣的是，CD133的高表达与K-RAS和B-Raf的突变有关，而抑制突变的K-RAS或下游丝裂原活化蛋白激酶(MEK)信号会降低CD133的表达。此外，激活的K-RAS基因表达特征可以预测CD133在我们的患者组以及其他类型的肿瘤数据组中的表达。结论：CD133在具有Ras-Raf-MEK-ERK途径过度激活的结直肠癌中表达上调，因此与K-Ras或B-Raf的突变有关。由于这两个基因的突变都与预后不良有关，我们认为CD133的表达与CSC的数量无关，而与Ras-Raf通路的突变或活性状态有关。临床癌症资源；18(11)；3132-41。(C)2012年AACR。
Purpose: High expression of cancer stem cell (CSC) marker CD133 has been used as a predictor for prognosis in colorectal cancer (CRC), suggesting that enumeration of CSCs, using CD133, is predictive for disease progression. However, we showed recently that both CD133 mRNA and protein are not down-regulated during differentiation of colon CSCs, pointing to an alternative reason for the prognostic value of CD133. We therefore set out to delineate the relation between CD133 expression and prognosis.Experimental Design: A CRC patient series was studied for expression of CD133 and other CSC markers by microarray and quantitative PCR analysis. In addition, several common mutations were analyzed to determine the relation with CD133 expression.Results: CD133 mRNA expression predicted relapse-free survival in our patient series, whereas several other CSC markers could not. Moreover, no correlation was found between expression of other CSC markers and CD133. Interestingly, high CD133 expression was related to mutations in K-Ras and B-Raf, and inhibition of mutant K-Ras or downstream mitogen-activated protein kinase kinase (MEK) signaling decreases CD133 expression. In addition, an activated K-Ras gene expression signature could predict CD133 expression in our patient set as well as data sets of other tumor types.Conclusion: CD133 expression is upregulated in CRC tumors that have a hyperactivated Ras-Raf-MEK-ERK pathway and is therefore related to mutations in K-Ras or B-Raf. As mutations in either gene have been related to poor prognosis, we conclude that CD133 expression is not indicative for CSC numbers but rather related to the mutation or activity status of the Ras-Raf pathway. Clin Cancer Res; 18(11); 3132-41. (C) 2012 AACR.