Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Room Na-617, 's-Gravendijkwal 230, 3015CE, Rotterdam, The Netherlands.
College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
J Mol Med (Berl). 2019 Jan;97(1):77-88. doi: 10.1007/s00109-018-1717-7. Epub 2018 Nov 19.
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.
干扰素 (IFNs) 具有抗病毒和免疫刺激功能，已广泛用于预防和治疗肝细胞癌 (HCC)。信号转导和转录激活因子 1 (STAT1) 是 IFN 信号的关键元件，而 STAT1 的功能则由其磷酸化状态决定。本研究旨在了解磷酸化 (p-) 和非磷酸化 (u-) STAT1 在 HCC 中的功能。我们发现，u-STAT1 在患者 HCC 肿瘤组织中显著升高，主要表达在细胞质中；而 p-STAT1 不存在。u-STAT1 的缺失可强力阻滞 HCC 细胞的细胞周期并抑制其生长。IFN-α 处理诱导的 p-STAT1 可有效触发干扰素刺激基因 (ISGs) 的表达，但对 HCC 细胞生长的影响适中。有趣的是，u-STAT1 和 p-STAT1 均可被 IFN-α 诱导，但具有不同的时间依赖性过程。此外，p-STAT1 和 u-STAT1 介导的 ISG 诱导模式也不同。重要的是，人工阻断 u-STAT1 的诱导，而不是 p-STAT1 的诱导，可使 HCC 细胞对 IFN 治疗敏感。因此，p-STAT1 和 u-STAT1 发挥双重功能，并协调调节 HCC 对 IFN 治疗的反应性。关键信息：STAT1 在 HCC 中上调，主要表现为 u-STAT1，而 p-STAT1 不存在。u-STAT1 维持 HCC 生长，而 p-STAT1 抑制 HCC 生长。STAT1 磷酸化状态的动态变化控制对 IFN 治疗的反应性。
