ArticleCell death and differentiation2025
Hepatic factor MANF drives hepatocytes reprogramming by detaining cytosolic CK19 in intrahepatic cholangiocarcinoma.
Article in Cell death and differentiation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- The role of mesencephalic astrocyte-derived neurotrophic factor in digestive diseases.Annals of medicine · 2026Review
- Targeting the Notch signaling pathway in digestive system cancers: from bench to bedside.Cancer cell international · 2026Review
- Proteomic Analysis of Paired FFPE Tissue and Extracellular Vesicles Reveals Proteins Associated with Recurrence in Stage II Colorectal Cancer.Journal of proteome research · 2026Article
- Notch signaling in liver diseases: mechanistic insights and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Immunotherapy targeting liver cancer tumor-initiating cells: challenges, mechanisms, and emerging therapeutic horizons.Frontiers in immunology · 2025Review
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17 authors.
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Abstract
Intrahepatic cholangiocarcinoma (ICC) is characterized by poor prognosis and limited treatment. Hepatocytes have been considered as one of the origins of ICC, however, the underlying mechanisms remain unclear. Here, we found mesencephalic astrocyte-derived neurotrophic factor (MANF), a hepatoprotective factor, was exceptionally upregulated in human ICC tissues and experimental mouse ICC models induced by sleeping beauty transposon (SBT) or thioacetamide (TAA) challenge. We identified MANF as a biomarker for distinguishing the primary liver cancer and verified the oncogenic role of MANF in ICC using cell lines overexpressing/knocked down MANF and mice specifically knocked in/out MANF in hepatocytes. Lineage tracing revealed that MANF promoted mature hepatocyte transformation into ICC cells. Mechanistically, MANF interacted with CK19 at Ser35 to suppress CK19 membrane recruitment. Cytosolic CK19 bound to AR domain of Notch2 intracellular domain (NICD2) to stabilize NICD2 protein level and trigger Notch signaling, which contributed to hepatocyte transformation to ICC cells. We uncover a novel profile of MANF and the original mechanism, which shed light on ICC diagnosis and intervention.
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