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. Electronic supplementary materialThe online version of this article (10.1007/s00109-018-1717-7) contains supplementary material, which is available to authorized users.

JAK/STAT signaling in hepatocellular carcinoma

“…In a recent study, the authors found that elevated expression of STAT1 without activation (i.e., unphosphorylated STAT1) was observed in HCC patients [68]. The presence of unphosphorylated STAT1 was able to sustain growth in HCC cell lines in vitro [68]. This is an important finding in guiding the development of drug targets against STAT1 as a therapeutic strategy.…”

“…Notably, the antitumorigenic properties of STAT1 correlate with the activity of STAT1 instead of the expression levels of the protein itself. In a recent study, the authors found that elevated expression of STAT1 without activation (i.e., unphosphorylated STAT1) was observed in HCC patients [68]. The presence of unphosphorylated STAT1 was able to sustain growth in HCC cell lines in vitro [68].…”

Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth

“…Expression of mRNA in different samples were measured according to the manufacturer's instructions [25]. GAPDH was considered as reference gene for normalization.…”

Interferon α in cancer immunoediting: From elimination to escape

“…As members of the IRDS gene classifier, MCL1, IFIT3 and ISG15/G1P2 upregulation were associated with constitutive STAT1 overexpression . Blocking u‐STAT1 expression, but not p‐STAT1, was sufficient to resensitize cancer cells to IFNα's tumoricidal effects …”

“…IFNα transiently raises the amount of intracellular phosphorylated STAT1 (p‐STAT1), which declines over time to yield high levels of u‐STAT1. Both p‐STAT1 and u‐STAT1 are dichotomous phosphorylation states of the ISG protein STAT1 . Cytosolic u‐STAT1 was shown to induce transcription of a distinct subset of ISGs produced late in response to type I IFNs—including STAT1 itself—regardless of IFN activation or STAT1 phosphorylation .…”