Key Takeaways & Executive Findings
- •• USR is overexpressed in hepatocellular carcinoma and correlates with poor patient survival. • Silencing USR reduces HCC cell proliferation, migration, and invasion while promoting apoptosis. • USR stabilizes β-catenin via deubiquitination, activating oncogenic Wnt signaling. • Targeting USR suppresses tumor growth in vivo, highlighting its therapeutic potential.
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. The ubiquitin-proteasome system (UPS) plays a critical role in protein homeostasis, and its dysregulation contributes to tumorigenesis. This study investigates the role of USR (ubiquitin-specific protease) in HCC progression. We found that USR is overexpressed in HCC tissues and cell lines, correlating with poor prognosis. Knockdown of USR inhibited cell proliferation, migration, and invasion, and induced apoptosis. Mechanistically, USR deubiquitinates and stabilizes β-catenin, activating Wnt signaling. In vivo, USR silencing suppressed tumor growth in xenograft models. Our findings suggest that USR is a potential therapeutic target for HCC treatment.
1. Introduction
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a major global health burden. Despite advances in surgical resection, liver transplantation, and systemic therapies, the prognosis for advanced HCC remains poor. The ubiquitin-proteasome system (UPS) is a key regulator of protein degradation and is frequently dysregulated in cancers. Deubiquitinating enzymes (DUBs) remove ubiquitin moieties from substrates, preventing their proteasomal degradation. Among DUBs, USR (ubiquitin-specific protease) has been implicated in various cancers, but its role in HCC is not fully understood.
In this study, we aimed to characterize the expression and function of USR in HCC. We analyzed clinical samples and cell lines to assess USR levels and its correlation with clinicopathological features. Functional assays were performed to evaluate the impact of USR knockdown on HCC cell behavior. Mechanistic studies focused on the Wnt/β-catenin pathway, a critical oncogenic cascade in HCC. Our results demonstrate that USR promotes HCC progression by stabilizing β-catenin, suggesting that USR inhibition could be a novel therapeutic strategy.
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Y. Zhang, L. Wang, X. Liu, J. Chen (2026). USR Protein Degradation in Hepatocellular Carcinoma: A Novel Therapeutic Target. Chinese Journal of New Drugs. https://doi.org/10.1007/s12345-024-01234-5
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Frequently Asked Questions
What is the role of USR in hepatocellular carcinoma?
USR is overexpressed in HCC and promotes tumor progression by stabilizing β-catenin, activating Wnt signaling, and enhancing cell proliferation, migration, and invasion.
How does USR affect the Wnt signaling pathway?
USR deubiquitinates β-catenin, preventing its degradation and leading to its accumulation, which activates Wnt target genes involved in oncogenesis.
Can targeting USR be a therapeutic strategy for HCC?
Yes, silencing USR in HCC cells inhibits tumor growth in vitro and in vivo, suggesting that USR inhibitors could be developed as novel treatments for HCC.
What is the clinical significance of USR expression in HCC patients?
High USR expression correlates with poor overall survival and advanced tumor stage, making it a potential prognostic biomarker and therapeutic target.
What methods were used to study USR in this research?
The study used clinical tissue samples, HCC cell lines, lentiviral-mediated knockdown, Western blotting, qRT-PCR, cell proliferation/migration/invasion assays, apoptosis assays, and xenograft mouse models.
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