Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling

• Published in: Cell death & disease 2021-10, Vol.12 (11), p.966-11, Article 966
• Main Authors: Shu, Yuke, Xu, Qing, Xu, Yahong, Tao, Qing, Shao, Mingyang, Cao, Xiaoyue, Chen, Yuwei, Wu, Zhenru, Chen, Menglin, Zhou, Yongjie, Zhou, Ping, Shi, Yujun, Bu, Hong
• Format: Article
• Language: English
• Subjects: 13/1; 13/105; 13/51; 13/89; 14/34; 14/63; 45/29; 631/67; 64/110; 692/699/67/1504/1610; 82/80; Ablation; Animal models; Animals; Antibodies; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - pathology; Biochemistry; Biomedical and Life Sciences; Body Weight; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Biology; Cell Culture; Cell fate; Cell Proliferation; Cholangiocarcinoma; Cholangiocarcinoma - genetics; Cholangiocarcinoma - pathology; Down-Regulation - genetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Immunology; Intracellular signalling; Ki-67 Antigen - metabolism; Life Sciences; Liver; Liver - pathology; Liver Cirrhosis - pathology; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastases; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Organ Size; Progenitor cells; Prognosis; Protein Domains; Receptors, Notch - chemistry; Receptors, Notch - metabolism; Secretase; Signal Transduction; Stem cells; Stem Cells - metabolism; Transcription Factor HES-1 - metabolism; Tumor cells; Tumor suppressor genes; Tumorigenesis
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04263-w

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.