Dichotomal functions of phosphorylated and unphosphorylated STAT1 in hepatocellular carcinoma

Buyun Ma,Jan N M Ijzermans,Kostandinos Sideras,Maikel P Peppelenbosch,Qiuwei Pan,Kan Chen,Wenshi Wang,Katharina Biermann,Wanlu Cao,Jiaye Liu,Dave Sprengers,Pengyu Liu,Jaap Kwekkeboom,Meng Li

doi:10.1007/s00109-018-1717-7

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 MessagesSTAT1 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.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors [1] and the second leading cause of cancerrelated death worldwide [2]
In order to investigate Signal transducer and activator of transcription 1 (STAT1) expression in HCC patients, we first searched the online datasets from Oncomine and GEO Datasets (GSE 14520), including six cohorts of 671 HCC tumor tissues with 585 tumor-free liver tissues
To further confirm these results, Tissue microarray (TMA) slides including tumor tissues and paired tumor-free liver tissues of 133 HCC patients were stained for STAT1

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors [1] and the second leading cause of cancerrelated death worldwide [2]. Chronic infection with hepatitis B or C virus (HBV or HCV) triggers liver fibrosis, cirrhosis, and eventually the development of HCC [3]. To prevent from or treat for viral hepatitis-related HCC, interferons (IFNs) have been explored in clinic [4, 5]. IFNs can be produced by various cell types, including immune cells, as well as tumor cells. They elicit antitumor effects by directly controlling tumor cells or indirectly by regulating immune response [6]. The pro-tumorigenic effect of IFNs, which may help the tumor escape the recognition of the immune system through

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