...
首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Differential Effects of Targeting Notch Receptors in a Mouse Model of Liver Cancer
【24h】

Differential Effects of Targeting Notch Receptors in a Mouse Model of Liver Cancer

机译:靶向Notch受体在肝癌小鼠模型中的差异作用。

获取原文
获取原文并翻译 | 示例
           

摘要

Primary liver cancer encompasses both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The Notch signaling pathway, known to be important for the proper development of liver architecture, is also a potential driver of primary liver cancer. However, with four known Notch receptors and several Notch ligands, it is not clear which Notch pathway members play the predominant role in liver cancer. To address this question, we utilized antibodies to specifically target Notch1, Notch2, Notch3, or jagged1 (Jag1) in a mouse model of primary liver cancer driven by v-akt murine thymoma viral oncogene homolog and neuroblastoma RAS viral oncogene homolog (NRas). We show that inhibition of Notch2 reduces tumor burden by eliminating highly malignant HCC- and CCA-like tumors. Inhibition of the Notch ligand, Jag1, had a similar effect, consistent with Jag1 acting in cooperation with Notch2. This effect was specific to Notch2, because Notch3 inhibition did not decrease tumor burden. Unexpectedly, Notch1 inhibition altered the relative proportion of tumor types, reducing HCC-like tumors but dramatically increasing CC-like tumors. Finally, we show that Notch2 and Jag1 are expressed in, and Notch2 signaling is activated in, a subset of human HCC samples. Conclusions: These findings underscore the distinct roles of different Notch receptors in the liver and suggest that inhibition of Notch2 signaling represents a novel therapeutic option in the treatment of liver cancer. (Hepatology 2015;61:942-952)
机译:原发性肝癌包括肝细胞癌(HCC)和胆管癌(CCA)。 Notch信号通路对肝结构的正确发育至关重要,它也是原发性肝癌的潜在驱动因素。然而,尚不清楚具有四个已知的Notch受体和几个Notch配体,哪些Notch通路成员在肝癌中起主要作用。为了解决这个问题,我们在v-akt鼠胸腺瘤病毒致癌基因同源物和成神经细胞瘤RAS病毒致癌基因同源物(NRas)驱动的原发性肝癌小鼠模型中利用抗体特异性靶向Notch1,Notch2,Notch3或jagged1(Jag1)。我们显示,通过消除高度恶性的HCC和CCA样肿瘤,Notch2抑制作用降低了肿瘤负担。对Notch配体Jag1的抑制具有相似的作用,与Jag1与Notch2协同作用一致。该作用是Notch2特有的,因为Notch3的抑制作用不会降低肿瘤负荷。出乎意料的是,Notch1抑制改变了肿瘤类型的相对比例,减少了HCC样肿瘤,但显着增加了CC样肿瘤。最后,我们显示Notch2和Jag1在人类HCC样本的子集中表达,并且Notch2信号被激活。结论:这些发现强调了不同的Notch受体在肝脏中的独特作用,并表明Notch2信号的抑制代表了在肝癌治疗中的一种新的治疗选择。 (肝病2015; 61:942-952)

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号