Underlying mechanism of sorafenib resistance in hepatocellular carcinoma: a bioinformatics study based on validated resistance-related genes

Background: Sorafenib, the first approved targeted therapy for advanced hepatocellular carcinoma (HCC), is often reported to comprised survival-benefit due to resistance. An underlying mechanism of resistance was proposed using bioinformatics analysis based on differentially expressed genes (DEGs) from microarrays. However, most DEGs were invalidated at both the expression level, and the role in causing resistance. Therefore, we conducted a bioinformatics analysis based on experimentally determined sorafenib-resistance-related genes (SRRGs) to elucidate the mechanism of sorafenib resistance. Methods: The SRRGs, which have been experimentally determined to promote or inhibit resistance, were collected from published studies. The Database for Annotation, Visualization and integrated Discovery (DAVID) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to perform Gene Ontology (GO) and pathway enrichment analysis, respectively. A corresponding protein-protein interaction network (PPI) was created using the Cytoscape software program, and network hub genes were proposed. Results: A total of 145 SRRGs, with 117 promoting and 28 inhibiting resistance, were identified. Cell proliferation, migration, development, response to oxygen levels, epithelial-to-mesenchymal transition (EMT), cell skeleton, protein function, and autophagy were all proposed as crucial gene functions related to resistance. The pathways related to cell proliferation or apoptosis, immune function, endocrine metabolism, stem cell function, and differentiation were identified as key resistance-related pathways. A total of 81 hub genes were proposed, including the following top 10 genes: TP53, AKT1, EGER, STAT3, VEGFA, JUN, MAPK1, IL6, PTEN, and CTNNB1. Conclusions: In conclusion, this study gathered experimentally validated genes that determine sorafenib resistance in HCC, provided an overview of the underlying mechanisms of resistance, and further validated sorafenib resistance in HCC.