麻木的
Notch信号通路
生物
癌症研究
细胞周期蛋白依赖激酶8
肺癌
Hes3信号轴
信号转导
细胞
干细胞
细胞生物学
细胞命运测定
癌变
癌症
病理
基因
遗传学
医学
转录因子
作者
Britta Westhoff,Ivan N. Colaluca,Dario Giorgini,Maddalena Donzelli,Daniela Tosoni,Sara Volorio,Giuseppe Pelosi,Lorenzo Spaggiari,Giovanni Mazzarol,Giuseppe Viale,Salvatore Pece,Pier Paolo Di Fiore
标识
DOI:10.1073/pnas.0907781106
摘要
Notch signaling regulates cell specification and homeostasis of stem cell compartments, and it is counteracted by the cell fate determinant Numb. Both Numb and Notch have been implicated in human tumors. Here, we show that Notch signaling is altered in approximately one third of non-small-cell lung carcinomas (NSCLCs), which are the leading cause of cancer-related deaths: in approximately 30% of NSCLCs, loss of Numb expression leads to increased Notch activity, while in a smaller fraction of cases (around 10%), gain-of-function mutations of the NOTCH-1 gene are present. Activation of Notch correlates with poor clinical outcomes in NSCLC patients without TP53 mutations. Finally, primary epithelial cell cultures, derived from NSCLC harboring constitutive activation of the Notch pathway, are selectively killed by inhibitors of Notch (gamma-secretase inhibitors), showing that the proliferative advantage of these tumors is dependent upon Notch signaling. Our results show that the deregulation of the Notch pathway is a relatively frequent event in NSCLCs and suggest that it might represent a possible target for molecular therapies in these tumors.
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