Important roles were disclosed for Numb in intrahepatic cholangiocarcinoma (iCCA) pathogenesis, according to a new study published in the journal Cell Death & Disease.

“Our results suggested that loss of Numb plays an important role in promoting [hepatic progenitor cell (HPC)] expansion, HPC malignant transformation, and, ultimately, iCCA development in chronically injured livers,” the study authors wrote.

Shu et al found the expression levels of Numb, a membrane protein known as a stem cell fate determinant, to be markedly downregulated in iCCA tissues when compared to paired adjacent noncancerous tissues. They observed a negative correlation between Numb expression levels and tumor differentiation.

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In addition, patients with low levels of Numb had shorter recurrence-free survival (RFS) and overall survival (OS) than patients with high levels of Numb.

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To further explore the role of Numb in iCCA pathogenesis, Shu et al used a mouse iCCA model. They observed a similar distribution of Numb between cancerous and noncancerous tissues to that found in humans.

Knockout experiments showed that Numb is involved in suppressing HPC expansion and periportal fibrosis upon chronic biliary injury. Its ablation promoted the growth, metastasis, and stemness of iCCA cells in vitro.

In contrast, loss of Numb did not affect liver development, homeostasis, and regeneration following a 70% partial hepatectomy.

The effects of Numb in iCCA are primarily related to Notch signaling. The findings by Shu et al indicated that Numb antagonizes the activity of the Notch pathway, though the mechanism is still unclear.

“In iCCA, Numb is likely involved in the regulation of nuclear translocation and degradation of [Notch intracellular domain (NICD)], thus regulating the Notch signaling pathway,” they explained.

Altogether, the results of the study suggest that Numb might be a potential new therapeutic target in iCCA.


Shu Y, Xu Q, Xu Y, et al. Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling. Cell Death Dis. 2021;12(11):966. doi:10.1038/s41419-021-04263-w