Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation
Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation
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DOI：
10.1158/0008-5472.can-04-1890
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发表时间：
2005-03-15
期刊：
影响因子：
11.2
通讯作者：
Fine, HA
中科院分区：
文献类型：
--
作者：
Purow, BW;Haque, RM;Fine, HA
Notch蛋白家族在决定细胞命运（如增殖、分化和凋亡）中起着不可或缺的作用。我们发现Notch-1及其配体Delta-like-1和jagded -1在许多胶质瘤细胞系和原发人胶质瘤中过表达。原发人胶质瘤组织阵列的免疫组织化学显示Notch-1细胞内结构域的细胞核中存在，表明Notch-1在原位激活。RNA干扰下调Notch-1、delta -样-1或Jagged-1可诱导多种胶质瘤细胞系凋亡并抑制增殖。此外，Notch-1或delta - like1小干扰RNA预处理胶质瘤细胞可显著延长小鼠原位脑肿瘤模型的存活时间。这些结果首次表明，癌细胞依赖于单个Notch配体；他们还提示在胶质瘤中可能存在Notch近分泌/自分泌环。Notch-1及其配体可能为胶质瘤的治疗提供新的靶点。
The Notch family of proteins plays an integral role in determining cell fates, such as proliferation, differentiation, and apoptosis. We show that Notch-1 and its ligands, Delta-like-1 and Jagged-1, are overexpressed in many glioma cell lines and primary human gliomas. Immunohistochemistry of a primary human glioma tissue array shows the presence in the nucleus of the Notch-1 intracellular domain, indicating Notch-1 activation in situ. Down-regulation of Notch-1, Delta-like- 1, or Jagged-1 by RNA interference induces apoptosis and inhibits proliferation in multiple glioma cell lines. In addition, pretreatment of glioma cells with Notch-1 or Delta-like-1 small interfering RNA significantly prolongs survival in a murine orthotopic brain tumor model. These results show, for the first time, the dependence of cancer cells on a single Notch ligand; they also suggest a potential Notch juxtacrine/autocrine loop in gliomas. Notch-1 and its ligands may present novel therapeutic targets in the treatment of glioma.