Integrated analysis identifies a platinum resistance-related prognostic signature for overall survival in hepatocellular carcinoma

This study aimed to identify prognostically relevant genes from a platinum resistance-related pathway and to develop a concise signature for predicting overall survival (OS) in patients with hepatocellular carcinoma (HCC). We conducted an integrated bioinformatics analysis using transcriptomic and clinical data from HCC patients in The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. The prognostic relevance of 70 platinum resistance-related genes (PRRGs) was evaluated, leading to the identification of BIRC5, BAK1, and MSH2 as components of a Platinum Resistance-Related Prognostic Signature (PRPS). The PRPS was developed using least absolute shrinkage and selection operator (LASSO) Cox regression and evaluated using Kaplan-Meier analysis, time-dependent receiver operating characteristic curves, and multivariable Cox regression. Functional enrichment, genomic alteration, and computational immune infiltration analyses were performed to characterize the biological context associated with the PRPS. In vitro experiments evaluated the effects of BIRC5, BAK1, and MSH2 on HCC cell proliferation and oxaliplatin sensitivity. The three-gene PRPS significantly stratified OS in the TCGA training cohort and the ICGC and GSE14520 validation cohorts. Functional enrichment and protein-protein interaction analyses indicated associations with cell-cycle regulation, apoptosis, and DNA repair. ssGSEA and CIBERSORT analyses showed distinct immune-cell infiltration patterns between the high- and low-PRPS groups, supporting an association between the PRPS and the tumor immune microenvironment. Knockdown of MSH2, BAK1, or BIRC5 inhibited PLC/PRF/5 cell proliferation and increased sensitivity to oxaliplatin. The BIRC5-, BAK1-, and MSH2-based PRPS provides a concise tool for OS stratification in HCC and is associated with distinct immune infiltration patterns. Functional experiments further link these genes to HCC cell proliferation and oxaliplatin sensitivity. These findings support further prospective and mechanistic validation of the PRPS.