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Review
. 2021 Nov 25:8:1415-1444.
doi: 10.2147/JHC.S336858. eCollection 2021.

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways

Mahshid Deldar Abad Paskeh  1   2 , Sepideh Mirzaei  3 , Milad Ashrafizadeh  4   5 , Ali Zarrabi  5   6 , Gautam Sethi  7   8
Affiliations
Review

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways

Mahshid Deldar Abad Paskeh et al. J Hepatocell Carcinoma. .

Abstract

Liver cancers cause a high rate of death worldwide and hepatocellular carcinoma (HCC) is considered as the most common primary liver cancer. HCC remains a challenging disease to treat. Wnt/β-catenin signaling pathway is considered a tumor-promoting factor in various cancers; hence, the present review focused on the role of Wnt signaling in HCC, and its association with progression and therapy response based on pre-clinical and clinical evidence. The nuclear translocation of β-catenin enhances expression level of genes such as c-Myc and MMPs in increasing cancer progression. The mutation of CTNNB1 gene encoding β-catenin and its overexpression can lead to HCC progression. β-catenin signaling enhances cancer stem cell features of HCC and promotes their growth rate. Furthermore, β-catenin prevents apoptosis in HCC cells and increases their migration via triggering EMT and upregulating MMP levels. It is suggested that β-catenin signaling participates in mediating drug resistance and immuno-resistance in HCC. Upstream mediators including ncRNAs can regulate β-catenin signaling in HCC. Anti-cancer agents inhibit β-catenin signaling and mediate its proteasomal degradation in HCC therapy. Furthermore, clinical studies have revealed the role of β-catenin and its gene mutation (CTNBB1) in HCC progression. Based on these subjects, future experiments can focus on developing novel therapeutics targeting Wnt/β-catenin signaling in HCC therapy.

Keywords: Wnt signaling; drug resistance; immunotherapy; liver cancer; non-coding RNAs.

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Conflict of interest statement

The authors declare no conflicts of interest for this work.

Figures

Figure 1
Figure 1
The canonical pathway of Wnt signaling.
Figure 2
Figure 2
β-catenin association with stemness and proliferation rate of HCC cells.
Figure 3
Figure 3
β-catenin signaling in regulation of HCC metastasis.
Figure 4
Figure 4
β-catenin signaling determines therapy response of HCC cells.
Figure 5
Figure 5
The ncRNAs modulate β-catenin signaling in HCC.
Figure 6
Figure 6
Selected anti-tumor compounds targeting β-catenin signaling in HCC therapy.
See this image and copyright information in PMC

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