An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors
An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors
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DOI：
10.1038/ng.127
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发表时间：
2008-05-01
期刊：
影响因子：
30.8
通讯作者：
Weinberg, Robert A.
中科院分区：
文献类型：
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作者：
Ben-Porath, Ittai;Thomson, Matthew W.;Weinberg, Robert A.
癌细胞具有与正常干细胞相似的特征。然而，尚不清楚这些表型相似性是否反映了共同分子途径的活性。在这里，我们分析了在各种人类肿瘤类型的表达谱中与胚胎干（ES）细胞身份相关的基因集的富集模式。我们发现组织学上低分化的肿瘤表现出通常在胚胎干细胞中富集的基因的优先过表达，并结合Polycomb调控基因的优先抑制。此外，Nanog、Oct4、Sox2和c-Myc的激活靶点在低分化肿瘤中比在高分化肿瘤中更频繁地过表达。在乳腺癌中，这种es样特征与高级别雌激素受体（ER）阴性肿瘤相关，通常为基底样亚型，临床预后较差。ES信号也存在于低分化胶质母细胞瘤和膀胱癌中。我们确定了在低分化肿瘤中高度表达的胚胎干细胞相关转录调控子子集。我们的研究结果揭示了与胚胎干细胞身份相关的基因与肿瘤的组织病理学特征之间以前未知的联系，并支持这些基因有助于许多肿瘤显示的干细胞样表型的可能性。
Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem ( ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb- regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor ( ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell-like phenotypes shown by many tumors.