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.

Additional Metadata
Keywords Hepatocellular carcinoma (HCC), Immune response, Interferon (IFN) signaling, Signal transducer and activator of transcription 1 (STAT1)
Persistent URL dx.doi.org/10.1007/s00109-018-1717-7, hdl.handle.net/1765/112349
Journal Journal of Molecular Medicine
Citation
Ma, B. (Buyun), Chen, K. (Kan), Liu, P, Li, M. (Meng), Liu, J. (Jiaye), 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