Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
EMBO J. 2010 Aug 4;29(15):2659-74. doi: 10.1038/emboj.2010.137. Epub 2010 Jun 25.
A cohort of genes associated with embryonic stem (ES) cell behaviour, including NANOG, are expressed in a number of human cancers. They form an ES-like signature we first described in glioblastoma multiforme (GBM), a highly invasive and incurable brain tumour. We have also shown that HEDGEHOG-GLI (HH-GLI) signalling is required for GBM growth, stem cell expansion and the expression of this (ES)-like stemness signature. Here, we address the function of NANOG in human GBMs and its relationship with HH-GLI activity. We find that NANOG modulates gliomasphere clonogenicity, CD133(+) stem cell cell behavior and proliferation, and is regulated by HH-GLI signalling. However, GLI1 also requires NANOG activity forming a positive loop, which is negatively controlled by p53 and vice versa. NANOG is essential for GBM tumourigenicity in orthotopic xenografts and it is epistatic to HH-GLI activity. Our data establish NANOG as a novel HH-GLI mediator essential for GBMs. We propose that this function is conserved and that tumour growth and stem cell behaviour rely on the status of a functional GLI1-NANOG-p53 network.
一组与胚胎干细胞（ES）行为相关的基因，包括 NANOG，在多种人类癌症中表达。它们形成了我们在多形性成胶质细胞瘤（GBM）中首次描述的 ES 样特征，GBM 是一种高度侵袭性和无法治愈的脑肿瘤。我们还表明，HEDGEHOG-GLI（HH-GLI）信号对于 GBM 的生长、干细胞的扩增和这种（ES）样干性特征的表达是必需的。在这里，我们研究了 NANOG 在人类 GBM 中的功能及其与 HH-GLI 活性的关系。我们发现 NANOG 调节神经胶质瘤球体的克隆形成能力、CD133(+)干细胞的行为和增殖，并且受 HH-GLI 信号的调节。然而，GLI1 也需要 NANOG 活性形成正反馈回路，该回路受 p53 的负调控，反之亦然。NANOG 对于 GBM 在原位异种移植中的致瘤性是必需的，并且它与 HH-GLI 活性具有上位性。我们的数据确立了 NANOG 作为 GBM 的新型 HH-GLI 介质的重要性。我们提出，这种功能是保守的，肿瘤生长和干细胞行为依赖于功能性 GLI1-NANOG-p53 网络的状态。
