Identification of prognostic biomarkers and correlations with immune infiltrates among cGAS-STING in hepatocellular carcinoma

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 this 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.

Clinical features ofDDX41mutation-related diseases: a systematic review with individual patient data

“…We excluded 77 publications, including 41 animal studies, 20 about irrelevant subjects, 13 reviews, and three in languages other than English and Chinese. The remaining 30 were next given full-text reviews and all were considered eligible for this study, including nine case series, 12 , 14 – 21 11 case reports, 22 – 32 four reports about DDX41 -related solid cancers, 33 – 36 and six rare case reports 37 – 42 ( Figure 1 ). No extra study was identified from the references listed in the relevant reviews and the included studies.…”

“…DDX41 has not yet been identified as a possible pathogenic variant in cases of solid cancers. Nonetheless, elevated DDX41 expression was reported to be associated with pathological grades, clinical stages, and thus worse prognosis, for example, shorter OS and less progression-free survival (PFS), at least in human colorectal cancer, 33 hepatocellular cancer, 34 breast cancer, 35 and clear cell renal cell carcinoma. 36…”

The cGAS-STING Pathway: Novel Perspectives in Liver Diseases

“…It was reported that low levels of STING in tumor tissues were associated with poor prognosis in HCC patients ( 89 ). Activation of the cGAS-STING pathway augmented immune cell infiltration in HCC tissues ( 90 ). The cGAS-STING pathway members also displayed strong associations with immune markers involved in clinical stages, pathological grades, and overall survival in patients with HCC ( 90 ), suggesting that the cGAS-STING pathway members could be used as potential prognostic biomarkers in patients with HCC.…”

“…Activation of the cGAS-STING pathway augmented immune cell infiltration in HCC tissues ( 90 ). The cGAS-STING pathway members also displayed strong associations with immune markers involved in clinical stages, pathological grades, and overall survival in patients with HCC ( 90 ), suggesting that the cGAS-STING pathway members could be used as potential prognostic biomarkers in patients with HCC. In a mouse model of mutagen-induced HCC, STING deficiency reduced phosphorylated-STAT1, autophagy, and cleaved caspase 3 levels but accelerated tumor progression, with increased numbers of large tumors at advanced stages.…”

Immunological characterization of hepatocellular carcinoma

“…More recently, the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway has emerged in the field of HCC research for its potential as a therapeutic target. The cGAS-STING pathway activates the innate immune response in response to DNA products, from both foreign pathogens and self-DNA released due to cell damage [121] . It has been shown that low cGAS-STING activation is associated with reduced survival in HCC, lung adenocarcinoma, and gastric cancers [122] .…”