Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling.
Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling.
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麻木丧失通过增强Notch信号传导促进肝祖细胞扩张和肝内胆管癌。
DOI：
10.1038/s41419-021-04263-w
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发表时间：
2021-10-19
影响因子：
9
通讯作者：
Bu H
中科院分区：
文献类型：
--
作者：
Shu Y;Xu Q;Xu Y;Tao Q;Shao M;Cao X;Chen Y;Wu Z;Chen M;Zhou Y;Zhou P;Shi Y;Bu H
Numb是一种干细胞命运决定因子，具有肿瘤抑制作用，与多种恶性肿瘤密切相关。肝内胆管细胞癌（iCCA）起源于肝祖细胞（HPC）;然而，Numb在HPC恶性转化和iCCA发展中的作用仍不清楚。一项回顾性队列研究表明，肿瘤组织中的Numb经常降低，表明iCCA患者的预后不良。一致地，在化学诱导的iCCA小鼠模型中，与正常胆管细胞相比，Numb在肿瘤细胞中下调。在饮食诱导的慢性肝损伤小鼠模型中，Numb消融显著促进组织学损伤、HPC扩张和肿瘤发生。类似地，培养的iCCA细胞中的Numb沉默增强细胞球状体生长、侵袭、转移和干细胞标志物的表达。在机制上，发现Numb与Notch细胞内结构域（NICD）结合，Numb消融促进Notch信号传导;当Notch信号传导被γ-分泌酶抑制剂治疗阻断时，这种作用被逆转。我们的研究结果表明，Numb的丢失在促进HPC扩张、HPC恶性转化以及最终在慢性损伤的肝脏中的iCCA发展中起重要作用。靶向抑制的Numb的疗法有希望用于治疗iCCA。
Numb, a stem cell fate determinant, acts as a tumor suppressor and is closely related to a wide variety of malignancies. Intrahepatic cholangiocarcinoma (iCCA) originates from hepatic progenitors (HPCs); however, the role of Numb in HPC malignant transformation and iCCA development is still unclear. A retrospective cohort study indicated that Numb was frequently decreased in tumor tissues and suggests poor prognosis in iCCA patients. Consistently, in a chemically induced iCCA mouse model, Numb was downregulated in tumor cells compared to normal cholangiocytes. In diet-induced chronic liver injury mouse models, Numb ablation significantly promoted histological impairment, HPC expansion, and tumorigenesis. Similarly, Numb silencing in cultured iCCA cells enhanced cell spheroid growth, invasion, metastasis, and the expression of stem cell markers. Mechanistically, Numb was found to bind to the Notch intracellular domain (NICD), and Numb ablation promoted Notch signaling; this effect was reversed when Notch signaling was blocked by γ-secretase inhibitor treatment. Our results suggested that loss of Numb plays an important role in promoting HPC expansion, HPC malignant transformation, and, ultimately, iCCA development in chronically injured livers. Therapies targeting suppressed Numb are promising for the treatment of iCCA.
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影响因子：
64.8
作者：
Colaluca, Ivan N.;Tosoni, Daniela;Di Fiore, Pier Paolo
通讯作者：
Di Fiore, Pier Paolo
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Barth JM;Köhler K
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82.9
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
3
作者：
Kokuryo, Toshio;Yokoyama, Yukihiro;Nagino, Masato
通讯作者：
Nagino, Masato