Notch signaling contributes to the pathogenesis of human osteosarcomas
Notch signaling contributes to the pathogenesis of human osteosarcomas
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DOI：
10.1093/hmg/ddp057
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发表时间：
2009-04-15
影响因子：
3.5
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
--
作者：
Engin, Feyza;Bertin, Terry;Lee, Brendan
Notch信号在发育过程和成体组织稳态中起着重要作用。改变的Notch信号传导与包括癌症在内的各种疾病有关。虽然已经确定了改变的Notch信号传导在造血和上皮来源的癌症中的重要性，但其在间充质来源的肿瘤中的作用尚不清楚。在这里，我们报告了人骨肉瘤细胞系和原发性人骨肉瘤肿瘤样本显示Notch及其靶基因和Osterix的显著上调。通过γ-分泌酶抑制剂或通过使用慢病毒介导的显性负性Mastermind样蛋白（DN-MAML）表达抑制Notch可降低体外骨肉瘤细胞增殖。在体内，裸鼠中建立的人肿瘤异种移植物在Notch信号传导的化学或遗传抑制后显示出肿瘤生长减少。最后，来自p53突变小鼠的骨肉瘤的转录谱分析证实了Notch 1靶基因Hes 1、Hey 1及其配体Dll 4的上调。我们的数据表明，Notch信号的激活有助于人类骨肉瘤的发病机制，其抑制可能是治疗这种间叶肿瘤的治疗方法。
Notch signaling plays an important role in developmental processes and adult tissue homeostasis. Altered Notch signaling has been associated with various diseases including cancer. While the importance of altered Notch signaling in cancers of hematopoietic and epithelial origins has been established, its role in tumors of mesenchymal origin is less clear. Here, we report that human osteosarcoma cell lines and primary human osteosarcoma tumor samples show significant up-regulation of Notch, its target genes and Osterix. Notch inhibition by gamma-secretase inhibitors or by using lentiviral mediated expression of dominant negative Mastermind-like protein (DN-MAML) decreases osteosarcoma cell proliferation in vitro. In vivo, established human tumor xenografts in nude mice show decreased tumor growth after chemical or genetic inhibition of Notch signaling. Finally, transcriptional profiling of osteosarcomas from p53 mutant mice confirmed up-regulation of Notch1 target genes Hes1, Hey1 and its ligand Dll4. Our data suggest that activation of Notch signaling contributes to the pathogenesis of human osteosarcomas and its inhibition may be a therapeutic approach for the treatment of this mesenchymal tumor.