Combining Transarterial Chemoembolisation With Reduced Deubiquitinase Activity Reduces Hepatocellular Carcinoma...

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) remains a significant global health challenge.
• Transarterial chemoembolisation (TACE) is a standard treatment, but its efficacy is limited.
• Understanding molecular mechanisms driving HCC progression and immune evasion is crucial for novel therapeutic strategies.

Purpose of the Study:

• To investigate the interaction between ubiquitin-specific protease 21 (USP21) and programmed death-ligand 1 (PD-L1) in HCC.
• To explore the potential of combining USP21 silencing with TACE for enhanced HCC treatment.
• To elucidate the role of USP21 in regulating PD-L1 stability and its impact on HCC progression.

Main Methods:

• USP21 was silenced in HCC cell lines and in diethylnitrosamine (DEN)-induced and HepG2 xenograft mouse models.
• The effects of USP21 knockdown, TACE, and their combination on tumor growth, proliferation, invasion, and apoptosis were assessed.
• USP21-PD-L1 interaction and deubiquitination were analyzed using co-immunoprecipitation and deubiquitination assays; rescue experiments involved PD-L1 overexpression.

Main Results:

• USP21 knockdown inhibited HCC cell proliferation and invasion.
• Combination therapy (TACE + USP21 knockdown) significantly improved anti-tumor effects compared to monotherapies.
• USP21 directly interacted with and deubiquitinated PD-L1, stabilizing its expression and prolonging its half-life.
• PD-L1 overexpression reversed the inhibitory effects of USP21 silencing and the enhanced therapeutic efficacy of the combination therapy.

Conclusions:

• USP21 stabilizes PD-L1 expression via deubiquitination, contributing to HCC progression and immune evasion.
• USP21 silencing enhances TACE therapeutic efficacy by modulating PD-L1 levels.
• Combining USP21 inhibition with TACE presents a promising combinatorial strategy for HCC treatment.