1. Dichotomal functions of phosphorylated and unphosphorylated STAT1 in hepatocellular carcinoma.
- Author
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Ma, Buyun, Chen, Kan, Liu, Pengyu, Li, Meng, Liu, Jiaye, Sideras, Kostandinos, Sprengers, Dave, Biermann, Katharina, Wang, Wenshi, IJzermans, Jan N. M., Cao, Wanlu, Kwekkeboom, Jaap, Peppelenbosch, Maikel P., and Pan, Qiuwei
- Subjects
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INTERFERONS , *LIVER cancer , *PHOSPHORYLATION , *STAT proteins , *CANCER cell growth - Abstract
Abstract: Interferons (IFNs) with antiviral and immune-stimulatory functions have been widely used in prevention and treatment of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 1 (STAT1) is a key element of the IFN signaling, and the function of STAT1 is critically determined by its phosphorylation state. This study aims to understand the functions of phosphorylated (p-) and unphosphorylated (u-) STAT1 in HCC. We found that u-STAT1 is significantly elevated in patient HCC tumor tissues and predominantly expressed in cytoplasm; while p-STAT1 is absent. Loss of u-STAT1 potently arrested cell cycle and inhibited cell growth in HCC cells. Induction of p-STAT1 by IFN-α treatment effectively triggers the expression of interferon-stimulated genes (ISGs), but has moderate effect on HCC cell growth. Interestingly, both u-STAT1 and p-STAT1 are induced by IFN-α, through with distinct time-dependent process. Furthermore, the ISG induction patterns mediated by p-STAT1 and u-STAT1 are also distinct. Importantly, artificial blocking of the induction of u-STAT1, but not p-STAT1, sensitizes HCC cells to treatment of IFNs. Therefore, p-STAT1 and u-STAT1 exert dichotomal functions and coordinately regulate the responsiveness to IFN treatment in HCC.Key Messages: STAT1 is upregulated and predominantly presented as u-STAT1 in HCC, while p-STAT1 is absent.U-STAT1 sustains but p-STAT1 inhibits HCC growth.The dynamic change of phosphorylation state of STAT1 control the responsiveness to IFN treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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