Aspirin enhances IFN-α-induced growth inhibition and apoptosis of hepatocellular carcinoma via JAK1/STAT1 pathway

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Hepatocellular carcinoma (HCC) often exhibits resistance to interferon-alpha (IFN-α) therapy.
• Signal transducer and activator of transcription 1 (STAT1) is crucial for IFN-α's anti-tumor effects.
• Defects in STAT1 expression are linked to IFN-α resistance in tumors.

Purpose of the Study:

• To investigate if aspirin can improve IFN-α's anti-tumor efficacy in HCC by activating STAT1.
• To elucidate the molecular mechanisms by which aspirin might enhance IFN-α treatment.

Main Methods:

• In vitro studies on HCC cell lines and in vivo studies using nude mice models.
• Analysis of STAT1 and STAT3 phosphorylation.
• Assessment of Janus kinase 1 (JAK1) phosphorylation.
• Gene expression analysis of IFN-stimulated genes (ISGs), including X-linked inhibitor of apoptosis-associated factor-1 and G1P3.
• Evaluation of apoptosis-related protein expression (Bax) and caspase activation (caspase-9, caspase-3).

Main Results:

• Aspirin significantly enhanced IFN-α-induced anti-proliferation and apoptosis in HCC cells in vitro.
• Aspirin promoted tumor growth inhibition in vivo.
• Aspirin specifically enhanced IFN-α-induced STAT1 phosphorylation, not STAT3.
• Aspirin's effect on STAT1 phosphorylation was mediated by JAK1 activation.
• Aspirin-activated STAT1 modulated the transcription of pro- and anti-apoptotic ISGs, leading to increased Bax and caspase activation.

Conclusions:

• Aspirin enhances the anti-tumor effects of IFN-α in HCC by activating the STAT1 pathway.
• This mechanism involves JAK1-mediated STAT1 phosphorylation and subsequent modulation of ISG expression.
• Findings suggest a potential therapeutic strategy combining aspirin with IFN-α to overcome tumor resistance and improve HCC treatment outcomes.
• This approach may have implications for future IFN-α-based protein and gene therapies.