Identification of Hub Genes and Potential Molecular Mechanisms in Patients with HBV-Associated Acute Liver Failure

Abstract

Hepatitis B virus (HBV) infection is a major cause of acute liver failure (ALF) in China, and mortality rates are high among patients who do not receive a matched liver transplant. This study aimed to determine potential mechanisms involved in HBV-ALF pathogenesis. Gene expression profiles under access numbers GSE38941 and GSE14668 were downloaded from the Gene Expression Omnibus database, including cohorts of HBV-ALF liver tissue and normal samples. Differentially expressed genes (DEGs) with false discovery rates (FDR) <0.05 and |log2(fold change)| >1 as thresholds were screened using the Limma package. Gene modules associated with stable disease were mined using weighed gene co-expression network analysis (WGCNA). A co-expression network was constructed and DEGs were analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A gene-based network was constructed to explore major factors associated with disease progression. We identified 2238 overlapping DEGs as crucial gene cohorts in ALF development. Based on a WGCNA algorithm, 10 modules (modules 1-10) were obtained that ranged from 75 to 1078 genes per module. Cyclin-dependent kinase 1 ( CDK1), cyclin B1 ( CCNB1), and cell-division cycle protein 20 ( CDC20) hub genes were screened using the co-expression network. Furthermore, 17 GO terms and 6 KEGG pathways were identified, such as cell division, immune response process, and antigen processing and presentation. Two overlapping signaling pathways that are crucial factors in HBV-ALF were screened using the Comprehensive Toxicogenomics Database (CTD). Several candidate genes including HLA-E, B2M, HLA-DPA1, and SYK were associated with HBV-ALF progression. Natural killer cell-mediated cytotoxicity and antigen presentation contributed to the progression of HBV-ALF. The HLA-E, B2M, HLA-DPA1, and SYK genes play critical roles in the pathogenesis and development of HBV-ALF.

The spleen tyrosine kinase (SYK): A crucial therapeutic target for diverse liver diseases

“…SYK is related with various diseases, and participates in the regulation of numerous signal transduction in liver. For example, SYK is activated gradually during the progression of alcoholic or viral liver diseases, and therapeutically blocking SYK function by different chemical inhibitors significantly diminished alcohol-induced hepatic steatosis and viral hepatitis [ 7 , 41 , 43 ]. Moreover, the process of liver fibrosis is also accelerated by SYK activation, which promotes the development of liver cirrhosis and liver cancer eventually [ 7 , 44 ].…”

“…In virus infection-induced hepatitis, scientists have confirmed that the expression of SYK and cytokines in hepatocytes can be significantly upregulated by Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection, and the increased cytokines and SYK expression in hepatocytes further enhance the transcription of fibrosis-related genes in hepatic stellate cells (HSCs), the core participants in liver fibrosis [ 7 ]. Therefore, SYK plays an important role in the process form viral hepatitis to liver fibrosis, and it’s considered as an important therapeutic target for different viral hepatitis [ 43 , 46 ]. For example, the glypican-3 or E2 protein on HCV can bind to CD81 (the key receptor for HCV) and affect phosphorylation of Ezrin via SYK, leading to the activation of the Hippo signaling pathway and inhibition of yes-associated protein (YAP) signaling pathway in human hepatocytes [ 47 , 48 , 49 ].…”