Dichotomal functions of phosphorylated and unphosphorylated STAT1 in hepatocellular carcinoma

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2019-01, Vol.97 (1), p.77-88
• Main Authors: 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., Pan, Qiuwei
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cytoplasm; Hepatocellular carcinoma; Human Genetics; Humans; Immunologic Factors - pharmacology; Interferon; Interferon-alpha - pharmacology; Internal Medicine; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Molecular Medicine; Original; Original Article; Phosphorylation; Phosphorylation - drug effects; Signal Transduction - drug effects; Stat1 protein; STAT1 Transcription Factor - analysis; STAT1 Transcription Factor - metabolism; Transcription; α-Interferon
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-018-1717-7

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.