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

Yuke Shu,Yuwei Chen,Qing Xu,Hong Bu,Zhenru Wu,Qing Tao,Mingyang Shao,Xiaoyue Cao,Yongjie Zhou,Yahong Xu,Menglin Chen,Yujun Shi,Ping Zhou

doi:10.1038/s41419-021-04263-w

Abstract

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.

Highlights

Primary liver cancer (PLC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide according to the latest global cancer statistics [1]
Loss of Numb promotes hepatic progenitors (HPCs) expansion and liver fibrosis As Intrahepatic cholangiocarcinoma (iCCA) has long been suggested to be derived from HPCs [16, 17], we explored the role of Numb in HPC activation
Numb was positively expressed in both hepatocytes and cholangiocytes; in the iCCA tissues, Numb was markedly downregulated as indicated by positive cytokeratin 19 (CK19) staining but negative Numb staining (Fig. 1A and Fig. S1A)

Summary

Introduction

Primary liver cancer (PLC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide according to the latest global cancer statistics [1]. Intrahepatic cholangiocarcinoma (iCCA) accounts for 10–15% of PLCs, ranking as the second incidence rate of PLC after hepatocellular carcinoma (HCC). The incidence of iCCA has gradually increased in recent years [2,3,4]. Due to the occult incidence, early metastasis, and low resection rate, only 10%–15% of iCCA patients can receive radical resection [5,6,7]. It is urgent to dissect the precise molecular mechanisms of iCCA pathogenesis for targeted prevention and treatment. The pathogenesis of iCCA is still not completely clear, iCCA often shares many risk factors with HCC, such as liver cirrhosis and viral hepatitis [3, 8]. Cholestasis, parasite infection, radiation exposure, microenvironment damage, and metabolic syndrome are closely correlated with the development of iCCA [7, 9, 10]

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Conclusion