Identifying potential prognosis markers in hepatocellular carcinoma via integrated bioinformatics analysis and biological experiments

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Background: Hepatocellular carcinoma is one kind of clinical common malignant tumor with a poor prognosis, and its pathogenesis remains to be clarified urgently. This study was performed to elucidate key genes involving HCC by bioinformatics analysis and experimental evaluation. Methods: We identified common differentially expressed genes (DEGs) based on gene expression profile data of GSE60502 and GSE84402 from the Gene Expression Omnibus (GEO) database. Gene Ontology enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, REACTOME pathway enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were used to analyze functions of these genes. The protein-protein interaction (PPI) network was constructed using Cytoscape software based on the STRING database, and Molecular Complex Detection (MCODE) was used to pick out two significant modules. Hub genes, screened by the CytoHubba plug-in, were validated by Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas (HPA) database. Then, the correlation between hub genes expression and immune cell infiltration was evaluated by Tumor IMmune Estimation Resource (TIMER) database, and the prognostic values were analyzed by Kaplan-Meier plotter. Finally, biological experiments were performed to illustrate the functions of RRM2. Results: Through integrated bioinformatics analysis, we found that the upregulated DEGs were related to cell cycle and cell division, while the downregulated DEGs were associated with various metabolic processes and complement cascade. RRM2, MAD2L1, MELK, NCAPG, and ASPM, selected as hub genes, were all correlated with poor overall prognosis in HCC. The novel RRM2 inhibitor osalmid had anti-tumor activity, including inhibiting proliferation and migration, promoting cell apoptosis, blocking cell cycle, and inducing DNA damage of HCC cells. Conclusion: The critical pathways and hub genes in HCC progression were screened out, and targeting RRM2 contributed to developing new therapeutic strategies for HCC.

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