Novel Potential Peripheral ECM Biomarkers for Prognosis and Therapeutic Approaches in Liver Cirrhosis Based on Microarray Analysis

Liver cirrhosis is a significant global health concern, with incident cases rising by ۱۶.۷% from ۲۰۰۹ to ۲۰۱۹ and contributing to nearly ۱.۵ million deaths globally by ۲۰۱۹. Its pathogenesis involves excessive collagen deposition and extracellular matrix accumulation, leading to hepatocellular dysfunction and portal hypertension. Consequently, the identification of reliable biomarkers for diagnosis and prognosis has become paramount in clinical research. To address this urgent need, we utilized microarray analysis to examine gene expression profiles and identify differentially expressed genes (DEGs) associated with disease progression. Dataset GSE۹۷۰۸۳, obtained from the Geo database, includes ۱۰ male Wistar rat liver tissue samples, five normal control livers, and five cirrhotic liver models with DEN/TAA treatment. GEO۲R analysis confirmed dataset normalization, and DEGs were screened based on adjusted P-value < ۰.۰۵ and |logFC| ≥ ۱. A Protein-Protein Interaction Network of DEGs was constructed using the STRING database, beside Cytoscape software identified ۱۲ hub genes (Agxt, Plg, Apoa۵, Vtn, Akr۱c۶, Slc۲۷a۵, Serpinc۱, Lipc, Lcat, Hrg, Pon۱, Mbl۱) based on betweenness centrality (BC), closeness centrality (CC), eigenvector centrality (EGC), and degree centrality (DC). Expression locations of the hub genes were identified using UniProt and DAVID databases, with genes expressing intracellularly excluded. Based on literature review, from the eight genes with secreted products to ECM and expression in liver cells reported by Enrichr, a panel of four genes —Plg, Apoa۵, Mbl۱, and Serpinc۱ —was suggested as putative diagnostic and prognostic biomarkers for liver cirrhosis and potential therapeutic targets to mitigate its pathological features. The plasminogen (Plg) gene may be involved in processes related to liver cirrhosis and hepatocellular carcinoma (HCC). Overexpression in HBV-induced HCC is hypothesized to promote tumor progression via the Hippo signaling pathway through SRC activation. The Apolipoprotein A۵ (Apoa۵) gene, which is primarily associated with triglyceride metabolism, may enhance triglyceride hydrolysis and remnant lipoprotein clearance in plasma. Its intracellular role could potentially contribute to triglyceride-rich lipid droplet accumulation, aggravating non-alcoholic fatty liver disease (NAFLD). Elevated Apoa۵ expression is suggested to correlate with hepatic triglyceride storage in human and rat NAFLD livers. The Mannose-Binding Lectin (MBL) gene may play a role in immune defense and complement activation via the lectin pathway. Mutations in the MBL gene, particularly at codon ۵۴, are thought to be associated with the progression of chronic hepatitis B and increased risks of cirrhosis and spontaneous bacterial peritonitis. Lastly, the Serpin family C member ۱ (Serpinc۱) gene is hypothesized to

کلیدواژه ها:

Liver cirrhosis ، biomarkers ، microarray analysis ، gene expression ، differentially expressed genes ، Protein-Protein Interaction Network ، hub genes ، Plg ، Apoa۵ ، Mbl۱ ، Serpinc۱ ، liver cells ، therapeutic targets