Abstract
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway induces innate immunity by activating the production of inflammatory cytokines and type I interferons. Recently, studies revealed that self-DNA from by-products of chromosome instability and tumors could activate the cGAS-STING pathway, and subsequently promote or inhibit tumor development. However, the prognostic value and correlations with immune infiltrates of the cGAS-STING pathway in hepatocellular carcinoma (HCC) have not been clarified. In the present study, we used the Molecular Signatures Database, Oncomine, UALCAN, Human Protein Atlas, Kaplan–Meier plotter, LinkedOmics, and Tumor Immune Estimation Resource databases. Overexpression of XRCC5, IRF3, TRIM21, STAT6, DDX41, TBK1, XRCC6, TREX1, PRKDC, and TMEM173 was markedly correlated with clinical stages and pathological grades in HCC. Moreover, higher mRNA expression of XRCC5, XRCC6, and PRKDC was significantly related with shorter overall survival. However, higher mRNA expression of IFI16, STAT6, NLRC3, and TMEM173 was associated with favorable overall survival. Our results suggested that the kinase targets of the cGAS-STING pathway included the SRC family of tyrosine kinases (LCK and LYN), phosphoinositide 3-kinase-related protein kinase (PIKK) family kinases (ATM and ATR), and mitogen-activated protein kinase 1 (MAPK1). Furthermore, we identified significant correlations among the expression of cGAS-STING pathway and infiltration of B cells, CD4+T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells in HCC. The expression of the cGAS-STING pathway also exhibited strong relationships with diverse immune marker sets in HCC. These findings suggest that cGAS-STING pathway members may be used as prognostic biomarkers and immunotherapeutic targets HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide [1]
The results revealed that the mRNA expression of TRIM21, interferon gamma inducible protein 16 (IFI16), NLRC3, DEAD-box helicase 41 (DDX41)
The highest mRNA expression of IFI16 and TREX1 was found in grade 1 or 2; as the tumor grade increased, their mRNA expression tended to be lower (Figure 5D,J). These results suggested that XRCC5, interferon regulatory factor 3 (IRF3), TRIM21, Signal transducer and activator of transcription 6 (STAT6), DDX41, TANK-binding kinase 1 (TBK1), XRCC6, TREX1, PRKDC, and transmembrane protein 173 (TMEM173) were strongly correlated with tumorigenesis and tumor progression in patients with HCC
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide [1]. The 5-year survival rate of patients with advanced liver cancer is poor due to high tumor recurrence, metastasis, and the lack of early diagnostic biomarkers with high sensitivity and specificity [2]. Owing to poor liver function correlated with cirrhosis and extrahepatic metastasis, most patients with HCC are resistant to common cytotoxic therapies [3]. Doxorubicin was initially viewed as a first-choice drug for advanced HCC, a controlled trial showed that it was related with a low survival rate [4]. The overall life expectancy of patients with advanced HCC does not exceed 1 year even under treatment with sorafenib or regorafenib [5].there is an urgent need to identify novel potential prognostic and therapeutic targets that are related with tumor formation and progression in patients with HCC
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