Integrated Transcriptomic Analysis Revealed Hub Genes and Pathways Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC), a high mortality malignancy, has become a worldwide public health concern. Acquired resistance to the multikinase inhibitor sorafenib challenges its clinical efficacy and the survival benefits it provides to patients with advanced HCC. This study aimed to identify critical genes and pathways associated with sorafenib resistance in HCC using integrated bioinformatics analysis. Differentially expressed genes (DEGs) were identified using four HCC gene expression profiles (including 34 sorafenib-resistant and 29 sorafenib-sensitive samples) based on the robust rank aggregation method and R software. Gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. A protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING), and small molecules reversing sorafenib resistance were searched for using the connectivity map (CMAP) database. Pearson correlation and survival analyses of hub genes were performed using cBioPortal and Gene Expression Profiling and Interactive Analysis (GEPIA). Finally, the expression levels of hub genes in sorafenib-resistant HCC cells were verified using quantitative polymerase chain reaction (q-PCR). A total of 165 integrated DEGs (66 upregulated and 99 downregulated in sorafenib resistant samples compared sorafenib sensitive ones) primarily enriched in negative regulation of endopeptidase activity, extracellular exosome, and protease binding were identified. Some pathways were commonly shared between the integrated DEGs. Seven promising therapeutic agents and 13 hub genes were identified. These findings provide a strategy and theoretical basis for overcoming sorafenib resistance in HCC patients.

Identification of ferroptosis and drug resistance related hub genes to predict the prognosis in Hepatocellular Carcinoma

“…Nonetheless, our gene signature provides a more solid clinical reference in HCC by combining ferroptosis and drug- resistant phenotypes in a comprehensively prognosis-related analysis, which had a better predictive ability. Regarding the studies of drug resistance-related gene signature and pathways in HCC patients, Jiang, et al identified seven promising therapeutic agents and 13 hub genes related to sorafenib resistance in HCC by integrated transcriptomic analysis 33 . In addition, a great many miRNAs were directly involved in drug resistance in cancer cells 34 .…”

HMOX1 Attenuates the Sensitivity of Hepatocellular Carcinoma Cells to Sorafenib via Modulating the Expression of ABC Transporters

“…In GSE143233, Lin et al demonstrated that METTL3 was underexpressed in human sorafenib-resistant HCC and revealed that RNA m 6 A methylation mediated sorafenib resistance via FOXO3-mediated autophagy [ 23 ]. Jiang et al carried out integrated transcriptomic sequencing of GSE140202 and other datasets and identified 13 hub genes and seven promising therapeutic agents for HCC [ 18 ]. Li et al also performed bioinformatics analysis for GSE140202 and found that GINS1 was highly expressed in sorafenib-resistant HCC cells [ 24 ].…”

“…Liu et al analyzed dataset GSE109211 and proposed that HCC sorafenib resistance was correlated with identified hub genes and pathways [ 17 ]. Jiang et al analyzed GSE62813, GSE73571, GSE151412, and GSE140202 and found other key mediators in HCC sorafenib resistance [ 18 ].…”