PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype.
PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype.
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PTEN 缺陷将人类神经干细胞重新编程为胶质母细胞瘤干细胞样表型。
DOI：
10.1038/ncomms10068
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发表时间：
2015-12-03
影响因子：
16.6
通讯作者：
Liu GH
中科院分区：
文献类型：
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作者：
Duan S;Yuan G;Liu X;Ren R;Li J;Zhang W;Wu J;Xu X;Fu L;Li Y;Yang J;Zhang W;Bai R;Yi F;Suzuki K;Gao H;Esteban CR;Zhang C;Izpisua Belmonte JC;Chen Z;Wang X;Jiang T;Qu J;Tang F;Liu GH
PTEN是一种在许多类型的癌症中经常突变的肿瘤抑制因子。在这里，我们表明，有针对性的破坏PTEN导致肿瘤转化的人神经干细胞（NSC），但不是间充质干细胞。PTEN缺陷型NSC显示肿瘤相关的代谢和基因表达谱，并在免疫缺陷小鼠中产生颅内肿瘤。PTEN定位于NSC中的细胞核，通过与cAMP应答元件结合蛋白1（CREB）/CREB结合蛋白（CBP）结合而结合PAX 7启动子并抑制PAX 7转录。PTEN缺陷导致PAX 7的上调，这反过来又促进了NSC的致癌转化，并在人胶质母细胞瘤干细胞中保持“侵略性”。在一个大型临床数据库中，我们发现在PTEN缺陷的胶质母细胞瘤中PAX 7水平增加。此外，我们确定丝裂霉素C选择性地触发PTEN缺陷的神经干细胞凋亡。总之，我们揭示了PTEN如何保护NSC的潜在机制，并建立了一个细胞平台来识别参与NSC转化的因素，可能允许胶质母细胞瘤的个性化治疗。 肿瘤抑制因子PTEN在胶质母细胞瘤中经常发生突变或丢失。在这里，作者证明了在神经元干细胞中，PTEN反式抑制PAX 7基因表达，而PTEN缺陷促进PAX 7依赖性肿瘤转化。
PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficient mice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates ‘aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma. The tumor suppressor PTEN is often mutated or lost in glioblastoma. Here, the authors demonstrate that in neuronal stem cells PTEN trans-represses PAX7 gene expression and PTEN deficiency promotes PAX7-dependent neoplastic transformation.