机构：[1]Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu 610041, China四川大学华西医院[2]Laboratory ofTransplantation, West China Hospital, Sichuan University, Chengdu 610041, China四川大学华西医院[3]Department of Pathology, Sichuan Tumor Hospital, Chengdu 610041, China四川省肿瘤医院[4]Department ofPathology, West China Hospital, Sichuan University, Chengdu 610041, China四川大学华西医院
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 gamma-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.
基金：
Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [82072689, 81872019]; 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University [2020HXFH010]; Sichuan Province Science and Technology Planning Project [2018JY0653]
第一作者机构：[1]Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu 610041, China
共同第一作者：
通讯作者：
通讯机构：[1]Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu 610041, China[2]Laboratory ofTransplantation, West China Hospital, Sichuan University, Chengdu 610041, China
推荐引用方式(GB/T 7714)：
Shu Yuke,Xu Qing,Xu Yahong,et al.Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling[J].CELL DEATH & DISEASE.2021,12(11):doi:10.1038/s41419-021-04263-w.
APA：
Shu, Yuke,Xu, Qing,Xu, Yahong,Tao, Qing,Shao, Mingyang...&Bu, Hong.(2021).Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling.CELL DEATH & DISEASE,12,(11)
MLA：
Shu, Yuke,et al."Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling".CELL DEATH & DISEASE 12..11(2021)
生物学