Exosomal circ_0032704 confers sorafenib resistance to hepatocellular carcinoma and contributes to cancer malignant...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) is a major global health concern.
• Sorafenib is a first-line treatment for advanced HCC, but drug resistance remains a significant challenge.
• The role of circular RNAs (circRNAs) in HCC drug resistance is an emerging area of research.

Purpose of the Study:

• To investigate the function of circ_0032704 in the development of sorafenib resistance in HCC.
• To elucidate the underlying molecular mechanisms involving miR-514a-3p and programmed death-ligand 1 (PD-L1).
• To assess the potential of exosomal circ_0032704 as a diagnostic biomarker for HCC.

Main Methods:

• Quantitative real-time PCR (qPCR) and western blot were used to detect the expression of circ_0032704, miR-514a-3p, PD-L1, and related proteins.
• Cell viability, proliferation, migration, and invasion assays (CCK-8, EdU, wound healing, transwell) were performed.
• Dual-luciferase reporter, RIP, and pull-down assays confirmed the interaction between circ_0032704 and miR-514a-3p.
• Exosomes were isolated and characterized using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA).
• In vivo efficacy was evaluated using xenograft models in mice.

Main Results:

• Circ_0032704 was significantly overexpressed in sorafenib-resistant HCC tissues and cells.
• Knockdown of circ_0032704 decreased sorafenib resistance, inhibited proliferation, migration, and invasion in HCC cells.
• Circ_0032704 positively regulated PD-L1 expression by sponging miR-514a-3p.
• Overexpression of PD-L1 reversed the inhibitory effects of circ_0032704 knockdown.
• Inhibition of circ_0032704 within exosomes reduced sorafenib resistance and tumor growth in vivo.
• Exosomal circ_0032704 demonstrated stability and diagnostic value.

Conclusions:

• Circ_0032704 plays a crucial role in enhancing sorafenib resistance and promoting malignant progression in HCC.
• Circ_0032704 can be transported via exosomes, and exosomal circ_0032704 holds promise as a diagnostic biomarker for HCC.