Notch Signaling in Hepatocellular Carcinoma
Summary
Notch signalling is a conserved cell-to-cell communication pathway that regulates proliferation, differentiation and survival. In the liver, Notch receptors (Notch1–4) engage membrane-bound ligands to trigger sequential proteolytic cleavages, releasing the Notch intracellular domain (NICD). NICD translocates to the nucleus to modulate transcription of target genes such as HES and HEY families. In hepatocellular carcinoma (HCC), aberrant Notch activation is observed in a substantial subset of tumours and contributes to malignant hallmarks including enhanced cell division, epithelial–mesenchymal transition (EMT), cancer stem cell maintenance, angiogenesis and immune evasion. Notch signalling intersects with Wnt, TGFβ and PI3K–Akt pathways, creating a complex network that drives tumour progression. The stability of NICD is controlled by E3 ubiquitin ligases such as FBXW7 and by accessory proteins like ASPM, affecting the amplitude and duration of Notch output. Contextual factors determine whether Notch acts as an oncogene or tumour suppressor, with implications for patient prognosis. Clinically, pharmacological inhibitors of γ-secretase, monoclonal antibodies and decoy ligands are under investigation to modulate Notch activity in HCC, offering potential strategies to overcome drug resistance and improve outcomes.
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Notch Signaling in Hepatocellular Carcinoma publication trend
The graph below shows the total number of articles in notch signaling in hepatocellular carcinoma across all publications each year (not limited to Nature Index journals).
Technical terms
Notch intracellular domain (NICD): The active fragment of a Notch receptor released by proteolysis to regulate gene expression.
γ-Secretase: A multisubunit protease complex that cleaves Notch receptors within the membrane to liberate NICD.
E3 ubiquitin ligase: An enzyme that tags proteins with ubiquitin chains, marking them for proteasomal degradation (e.g., FBXW7).
Epithelial–mesenchymal transition (EMT): A process by which epithelial cells acquire mesenchymal characteristics, enhancing motility and invasiveness.
Tumour microenvironment: The surrounding cells, extracellular matrix and signalling molecules that influence tumour behaviour and treatment response.
References
- ASPM stabilizes the NOTCH intracellular domain 1 and promotes oncogenesis by blocking FBXW7 binding in hepatocellular carcinoma cells. Molecular Oncology (2024).
- An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma. Journal of Experimental & Clinical Cancer Research (2019).
- NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis. Oncogene (2020).
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