科研之友
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摘要
STAT1 has a key role in exerting the antiproliferative and proapoptotic effects of interferon (IFN)-alpha on tumors, and its defects in expression is associated with IFN-alpha resistance. In this study we want to investigate whether aspirin can improve the antitumor efficiency of IFN-alpha on hepatocellular carcinoma (HCC) through the activation of STAT1. We found that aspirin not only significantly enhanced IFN-alpha-induced antiproliferation and apoptosis of HCC in vitro study but also enhanced tumor growth inhibition in nude mice. Although IFN-alpha alone resulted in significant phosphorylation of both STAT1 and STAT3, aspirin only prompted the IFN-alpha-induced phosphorylation of STAT1. Further study revealed that aspirin-prompted phosphorylation of STAT1 was activated through phosphorylation of JAK1. Furthermore, aspirin-activated STAT1 upregulated the transcription of proapoptotic IFN-stimulated gene (ISG) of X-linked inhibitor of apoptosis-associated factor-1 and downregulated the transcription of antiapoptotic ISG of G1P3, which in turn promoted the expression of Bax and activation of caspase-9 and caspase-3, thereby sensitizing HCC cells to IFN-alpha-induced apoptosis. Taken together, our findings suggest a novel strategy of using aspirin to overcome tumor resistance and enhance the effectiveness of IFN-a in HCC treatment through activating STAT1 gene, and have potential implications for improving future IFN-alpha protein and gene therapy.
