Methylation of Cancer-Stem-Cell-Associated Wnt Target Genes Predicts Poor Prognosis in Colorectal Cancer Patients
Methylation of Cancer-Stem-Cell-Associated Wnt Target Genes Predicts Poor Prognosis in Colorectal Cancer Patients
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DOI：
10.1016/j.stem.2011.10.008
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发表时间：
2011-11-04
期刊：
影响因子：
23.9
通讯作者：
Medema, Jan Paul
中科院分区：
文献类型：
--
作者：
de Sousa e Melo, Felipe;Colak, Selcuk;Medema, Jan Paul
来源于癌症干细胞（CSC）的基因特征预测许多形式癌症的肿瘤复发。在这里，我们推导出了由高Wnt信号传导活性定义的结直肠CSC的基因特征，这与先前的观察结果一致，预测预后不良。然而，令人惊讶的是，我们发现Wnt靶基因的表达升高实际上与良好的预后相关，而Wnt靶基因表达低的患者肿瘤与未成熟干细胞特征分离。我们发现几个Wnt靶基因，包括ASCL2和LGR5，在肿瘤发生的进展过程中被CpG岛甲基化沉默，并且它们的重新表达与肿瘤生长减少相关。总之，我们的数据表明，Wnt靶基因的启动子甲基化是结直肠癌复发的一个强有力的预测因子，并表明CSC基因特征，而不是反映CSC数量，可能反映恶性组织的分化状态。
Gene signatures derived from cancer stem cells (CSCs) predict tumor recurrence for many forms of cancer. Here, we derived a gene signature for colorectal CSCs defined by high Wnt signaling activity, which in agreement with previous observations predicts poor prognosis. Surprisingly, however, we found that elevated expression of Wnt targets was actually associated with good prognosis, while patient tumors with low expression of Wnt target genes segregated with immature stem cell signatures. We discovered that several Wnt target genes, including ASCL2 and LGR5, become silenced by CpG island methylation during progression of tumorigenesis, and that their re-expression was associated with reduced tumor growth. Taken together, our data show that promoter methylation of Wnt target genes is a strong predictor for recurrence of colorectal cancer, and suggest that CSC gene signatures, rather than reflecting CSC numbers, may reflect differentiation status of the malignant tissue.