Dichotomal functions of phosphorylated and unphosphorylated STAT1 in hepatocellular carcinoma
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.
|Hepatocellular carcinoma (HCC), Immune response, Interferon (IFN) signaling, Signal transducer and activator of transcription 1 (STAT1)|
|Journal of Molecular Medicine|
|Organisation||Department of Gastroenterology & Hepatology|
Ma, B, Chen, K, Liu, P, Li, L, Liu, J, Sideras, K, … Pan, Q. (2018). Dichotomal functions of phosphorylated and unphosphorylated STAT1 in hepatocellular carcinoma. Journal of Molecular Medicine. doi:10.1007/s00109-018-1717-7