Wnt/β-Catenin Pathway Dynamics in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) frequently arises through aberrant activation of the canonical Wnt/β-catenin signalling cascade, a central regulator of cell fate, proliferation and survival. In healthy hepatocytes, binding of Wnt ligands to Frizzled and LRP5/6 co-receptors inhibits a cytoplasmic destruction complex (comprising AXIN1, APC and GSK3), allowing β-catenin to accumulate and translocate to the nucleus. There it partners with TCF/LEF transcription factors to induce targets such as c-Myc and Cyclin D1. In HCC, gain-of-function mutations in CTNNB1 or loss-of-function alterations in AXIN1 occur in roughly one third of tumours, yielding constitutive pathway activation. This drives tumour initiation, metabolic reprogramming, angiogenesis and metastatic dissemination. Beyond its transcriptional role, β-catenin also modulates plasma-membrane adhesion complexes and amplifies growth factor receptor signalling in a stage-dependent manner. The pathway’s dynamic localisation and multifaceted functions render it both a prognostic biomarker and a compelling therapeutic target in global HCC management.

Research from Nature Portfolio

Recent studies reveal that β-catenin functions evolve across HCC progression. In early-stage tumours, β-catenin is predominantly sequestered at the cell membrane in complex with cadherins, where it potentiates signalling through receptors such as EGFR to promote tumour cell survival. As disease advances, nuclear translocation of β-catenin becomes more pronounced, driving classical Wnt target gene expression and reinforcing proliferative and invasive phenotypes. This dual role underscores the need for temporal and spatial consideration when designing β-catenin-directed therapies, suggesting that selectively targeting membrane-associated versus nuclear activities may improve treatment specificity and efficacy.

Wnt/β-Catenin Pathway Dynamics in Hepatocellular Carcinoma publication trend

The graph below shows the total number of articles in wnt/β-catenin pathway dynamics in hepatocellular carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Wnt signalling pathway: A cellular communication cascade activated by Wnt ligands that stabilises β-catenin, enabling its nuclear role in gene regulation.

β-catenin: A dual-function protein; at the membrane it supports cell–cell adhesion, and when stabilised it translocates to the nucleus to activate transcription.

CTNNB1: The gene encoding β-catenin; oncogenic mutations here hinder degradation, leading to continuous pathway activation.

AXIN1: A scaffold protein in the β-catenin destruction complex whose inactivating mutations prevent β-catenin degradation.

Epithelial–mesenchymal transition (EMT): A process whereby epithelial cancer cells acquire motile, invasive properties crucial for metastasis.

Positive feedback loop: A self-reinforcing circuit in which β-catenin up-regulates factors that further stabilise or activate the pathway.

References

1. RGS19 activates the MYH9/β-catenin/c-Myc positive feedback loop in hepatocellular carcinoma. Experimental & Molecular Medicine (2024).
2. β-Catenin signaling in hepatocellular carcinoma. Journal of Clinical Investigation (2022).
3. Wnt/β-Catenin Signaling in Liver Cancers. Cancers (2019).
4. Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncology Letters (2014).
5. Promotion of growth factor signaling as a critical function of β-catenin during HCC progression. Nature Communications (2019).