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

Abstract

STAT1 has a key role in exerting the antiproliferative and proapoptotic effects of interferon (IFN)-α on tumors, and its defects in expression is associated with IFN-α resistance. In this study we want to investigate whether aspirin can improve the antitumor efficiency of IFN-α on hepatocellular carcinoma (HCC) through the activation of STAT1. We found that aspirin not only significantly enhanced IFN-α-induced antiproliferation and apoptosis of HCC in vitro study but also enhanced tumor growth inhibition in nude mice. Although IFN-α alone resulted in significant phosphorylation of both STAT1 and STAT3, aspirin only prompted the IFN-α-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-α-induced apoptosis. Taken together, our findings suggest a novel strategy of using aspirin to overcome tumor resistance and enhance the effectiveness of IFN-α in HCC treatment through activating STAT1 gene, and have potential implications for improving future IFN-α protein and gene therapy.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (grant number 30972889 and 30901444), the Independent Innovation Foundation of Shandong University (IIFSDU, grant number 2010TS030) and the Natural Science Foundation of Shandong Province (grant number ZR2010HM082).

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Correspondence to X-T Zhi.

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Li, T., Dong, ZR., Guo, ZY. et al. Aspirin enhances IFN-α-induced growth inhibition and apoptosis of hepatocellular carcinoma via JAK1/STAT1 pathway. Cancer Gene Ther 20, 366–374 (2013). https://doi.org/10.1038/cgt.2013.29

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