Notch3 drives development and progression of cholangiocarcinoma
Notch3 drives development and progression of cholangiocarcinoma
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DOI：
10.1073/pnas.1600067113
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发表时间：
2016-10-25
影响因子：
11.1
通讯作者：
Forbes, Stuart J.
中科院分区：
文献类型：
--
作者：
Guest, Rachel V.;Boulter, Luke;Forbes, Stuart J.
胆管癌的预后很差。Notch已被确定为一个潜在的驱动因素; Notch 1在肝细胞中的强制外源性过表达导致胆管肿瘤的形成。然而，在人类疾病中，尚不清楚肿瘤发生需要内源性信号通路的哪些组分，这些组分如何协调癌症，以及它们如何被靶向治疗。在这里，我们的特点Notch在人类切除的CC，在大鼠中的毒素驱动的模型，和转基因小鼠模型，其中p53缺失是针对胆管上皮和CC诱导使用肝癌的硫代乙酰胺。我们发现，在不同物种中，非典型受体NOTCH 3的表达存在差异;随着疾病的发展，它逐渐上调，并通过激活PI 3 k-Akt促进肿瘤细胞的存活。我们使用遗传KO研究表明，Notch 3缺失后肿瘤生长显著减弱，并证明信号传导通过非经典途径发生，不依赖于经典Notch，免疫球蛋白κ J区重组信号结合蛋白（RBPJ）的介体。这些数据为这种侵袭性癌症提供了选择性靶向Notch的机会，绕过了已知的RBPJ依赖性毒性。
The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of the mediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent.