Introduction
Hepatocellular carcinoma (HCC) is one of the deadliest cancers globally, with increasing incidence and mortality rates. It arises from chronic liver diseases, including hepatitis B or C infections, alcohol consumption, and metabolic disorders, often leading to liver cirrhosis. However, early detection is challenging as HCC is typically asymptomatic until advanced stages, limiting treatment options. While chemotherapy, immunotherapy, and targeted therapies are employed, their efficacy remains suboptimal. Thus, understanding the molecular mechanisms driving HCC is essential for developing new therapeutic strategies.
A growing body of research highlights the crucial role of the Wnt signaling pathway, especially its β-catenin axis, in HCC. This pathway regulates essential processes such as cell proliferation, migration, and immune evasion. This article reviews the involvement of the Wnt signaling pathway in HCC, its underlying mechanisms, and its potential as a therapeutic target.
Wnt Signaling Pathway
The Wnt signaling pathway is a conserved network that regulates cell proliferation, differentiation, and migration. It consists of the canonical Wnt/β-catenin pathway and non-canonical pathways such as Wnt/PCP and Wnt/Ca2+. In the canonical pathway, Wnt ligands bind to Frizzled receptors, stabilizing β-catenin, which accumulates in the cytoplasm and enters the nucleus. In the nucleus, β-catenin activates downstream genes like c-Myc and Cyclin D1, promoting cell proliferation and survival.
In HCC, mutations in key components of the Wnt pathway, including β-catenin (encoded by CTNNB1), AXIN, and APC, lead to sustained activation of this pathway. This dysregulation drives HCC progression by enhancing cell proliferation, migration, and immune evasion. Furthermore, extracellular vesicles (EVs) have been found to modulate Wnt signaling by delivering Wnt ligands and miRNAs, influencing tumor progression and immune response.
Molecular Mechanisms in HCC
Mutations in the CTNNB1 gene, which encodes β-catenin, lead to its stabilization and nuclear translocation, activating Wnt target genes and driving tumor growth. Additionally, mutations in AXIN and APC, which regulate β-catenin degradation, further enhance Wnt/β-catenin signaling. Research also reveals that EVs play a significant role in modulating this pathway. EVs can carry Wnt ligands, such as Wnt3a and Wnt5a, which bind to Frizzled receptors on recipient cells, further promoting tumor proliferation and metastasis. They also transport miRNAs that affect the Wnt signaling components, influencing tumor behavior.
Role of Wnt Signaling in HCC Pathogenesis
The Wnt/β-catenin pathway is essential for HCC development. Its activation promotes hepatocyte proliferation, inhibits apoptosis, and enhances tumor cell migration and invasion. β-catenin accumulation in the nucleus activates genes involved in cell cycle progression and survival, including c-Myc and Cyclin D1. Additionally, β-catenin inhibits pro-apoptotic genes like Bax and Bim, further supporting tumor cell survival.
The Wnt pathway also plays a role in epithelial-mesenchymal transition (EMT), which enables epithelial cells to acquire mesenchymal characteristics such as enhanced motility and invasiveness. This transition, regulated by Wnt signaling, promotes tumor cell migration, invasion, and metastasis. Additionally, the pathway influences angiogenesis by increasing the expression of vascular endothelial growth factor (VEGF), which supports tumor blood supply and further enhances metastatic potential.
Therapeutic Implications
Given the pivotal role of the Wnt/β-catenin pathway in HCC, targeting this signaling cascade holds significant promise. Several therapeutic strategies are being explored, including small molecule inhibitors, monoclonal antibodies, and gene therapies. β-catenin inhibitors, such as GSK-3β inhibitors, work by preventing β-catenin's nuclear translocation, thus inhibiting the activation of downstream genes involved in proliferation and survival.
Wnt competitive inhibitors, which block the binding of Wnt ligands to Frizzled receptors, also show promise in reducing Wnt pathway activation and inhibiting HCC growth. Clinical trials are underway to evaluate the safety and efficacy of these therapies. In addition, combination therapies targeting both the Wnt pathway and other aspects of the tumor microenvironment, such as immune checkpoint inhibitors or anti-angiogenic agents, may enhance therapeutic efficacy.
Conclusion
The Wnt/β-catenin pathway plays a central role in HCC initiation, progression, and metastasis. Mutations in β-catenin and other components like AXIN and APC lead to aberrant activation of this pathway, driving tumor growth and immune evasion. Targeting Wnt signaling offers a promising therapeutic strategy for HCC. Several inhibitors targeting β-catenin, Frizzled receptors, and other downstream components are currently being evaluated in clinical trials. Despite challenges such as pathway complexity and drug resistance, Wnt-targeted therapies, especially when combined with other treatments, hold potential for improving HCC treatment outcomes.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2024-00401
The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study's novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
