Exploring novel prognostic biomarkers and biologic processes involved in NASH, cirrhosis and HCC based on survival analysis using systems biology approach

There is an unmet need to develop medications or drug combinations which can stop advancement of NASH to liver cirrhosis and HCC. Therefore, identifying key biomarkers based on overall survival and the exploring biological processes involved in the pathogenesis and progression of NASH toward cirrhosis and HCC to improve therapeutic interventions is necessary. The microarray dataset from the GPL۱۳۶۶۷ platform was downloaded from the Gene Expression Omnibus (GEO). The inclusion criteria for the DEGs included an adjusted p-value <۰.۰۵ and a log(۲) fold change >۱. In the first step, protein-protein interaction (PPI) network of differentially expressed genes (DEGs) in every three groups (NASH, Cirrhosis and HCC) was constructed using STRING online database. In the second step, the DEGs of each group were imported to Cytoscape software separately, and the genes with Degree >۳ were selected. In the third step, the genes with Degree >۳ were imported to Gephi software (۰.۹.۲ version) and the genes with betweenness centrality >۰ were selected. Venn diagram of these genes was depicted for the NASH, cirrhotic and HCC groups. According to venn diagram, ۹۶ (NASH), ۳۰ (cirrhotic) and ۲۱۳ (HCC) genes were specifically upregulated (based on inclusion criteria). Among specific genes, ۲۲ (NASH), ۵ (cirrhotic) and ۸۲ (HCC) genes were with poor overall survival. The overlap among the ۳ groups (NASH, Cirrhosis and HCC) contained ۴ upregulated genes HLA-F, HLA-DPA۱, TPM۱ and YWHAZ. From ۴ upregulated genes, only YWHAZ gene was with poor overall survival. Probably, upregulated genes with poor overall survival in NASH and cirrhosis are the biomarkers and predictors for infecting NASH and Cirrhotic patients to HCC in future. In three groups (NASH, cirrhosis and HCC), YWHAZ gene was enriched in several biological processes including cytokine-mediated signaling pathway, negative regulation of programmed cell death, regulation of MAPK cascade, regulation of mRNA stability and cellular component assembly. The present study detected new candidate genes and key biological processes in NASH, cirrhosis and HCC based on overall survival and using in silico analysis. Therefore, performing in vitro and in vivo researches to verify the results is necessary

Keywords:

biomarker , overall survival , NASH , cirrhosis , HCC