Abstract
Innate and adaptive immune responses are critically associated with the progression of fibrosis in chronic liver diseases. In this study, we aim to identify a unique immune-related gene signature representing advanced liver fibrosis and to reveal potential therapeutic targets. Seventy-seven snap-frozen liver tissues with various chronic liver diseases at different fibrosis stages (1: n = 12, 2: n = 12, 3: n = 25, 4: n = 28) were subjected to expression analyses. Gene expression analysis was performed using the nCounter PanCancer Immune Profiling Panel (NanoString Technologies, Seattle, WA, USA). Biological meta-analysis was performed using the CBS Probe PINGSTM (CbsBioscience, Daejeon, Korea). Using non-tumor tissues from surgically resected specimens, we identified the immune-related, five-gene signature (CHIT1_FCER1G_OSM_VEGFA_ZAP70) that reliably differentiated patients with low- (F1 and F2) and high-grade fibrosis (F3 and F4; accuracy = 94.8%, specificity = 91.7%, sensitivity = 96.23%). The signature was independent of all pathological and clinical features and was independently associated with high-grade fibrosis using multivariate analysis. Among these genes, the expression of inflammation-associated FCER1G, OSM, VEGFA, and ZAP70 was lower in high-grade fibrosis than in low-grade fibrosis, whereas CHIT1 expression, which is associated with fibrogenic activity of macrophages, was higher in high-grade fibrosis. Meta-analysis revealed that STAT3, a potential druggable target, highly interacts with the five-gene signature. Overall, we identified an immune gene signature that reliably predicts advanced fibrosis in chronic liver disease. This signature revealed potential immune therapeutic targets to ameliorate liver fibrosis.
Highlights
Chronic liver diseases progress to liver cirrhosis, which affects 1–2% of people worldwide
There is a high death rate associated with cirrhosis, and patients die due to cirrhosisrelated complications, such as gastrointestinal bleeding or hepatocellular carcinoma (HCC), which develop in one-third of cirrhosis cases [1]
We identified a macrophage-associated, novel immune-related gene signature associated with advanced fibrosis
Summary
Chronic liver diseases progress to liver cirrhosis, which affects 1–2% of people worldwide. Several approaches to reduce liver fibrosis are under investigation in order to eradicate hepatic decompensation, HCC, and other. Biomedicines 2022, 10, 180 fatal complications of cirrhosis [2], no specific anti-fibrotic treatment is currently available. Recent strategies based on imaging and laboratory testing are not sufficiently predictive for identifying fibrotic progression and/or fibrogenic/carcinogenic activity in chronic liver diseases. Biomarkers with better reliability and sensitivity to predict liver fibrosis and patient outcomes are urgently required. Laboratory parameters, including the levels of serum albumin, bilirubin, and platelets, are within the normal range, and their smaller dynamic range is susceptible to non-specific variation, which makes them unreliable for predicting fibrosis progression or patient outcome [3]
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