A Chemotherapy Response-Related Gene Signature and DNAJC8 as Key Mediators of Hepatocellular Carcinoma Progression and Drug Resistance.

Abstract

Background: Chemotherapy resistance in hepatocellular carcinoma presents a significant challenge to improved patient outcomes. Identifying genes associated with chemotherapy response can enhance treatment strategies and prognostic models.

Methods: We analyzed the expression of chemotherapy response-related gene in hepatocellular carcinoma using TCGA and GSE109211 cohorts. We constructed a prognostic model using Least Absolute Shrinkage and Selection Operator (LASSO) analysis and assessed its efficacy using Kaplan-Meier survival analysis. Additionally, we evaluated the immune landscape and gene mutation profiles between different chemotherapy response-related gene (CRRG) subtypes. DNAJC8's role in hepatocellular carcinoma cell functions and chemotherapy resistance was further explored through gene knockdown experiments in vitro and in vivo.

Results: Differential expression analysis identified 220 common genes associated with chemotherapy response. The prognostic model incorporating seven key genes efficiently distinguished responders from non-responders and indicated poorer overall survival for the CRRG-high subtype. The CRRG value correlated with tumor stage and grade, and mutation profiles showed distinct patterns between CRRG subtypes. The CRRG-high subtype exhibited an immune-suppressive phenotype with higher expression of PD-L1 and CTLA-4. High DNAJC8 expression was linked to poor prognosis in multiple cohorts. Knocking down DNAJC8 significantly inhibited hepatocellular carcinoma cell proliferation, migration, invasion, and reduced sorafenib IC50.

Conclusion: The seven-gene CRRG model, particularly DNAJC8, holds potential for predicting chemotherapy response and serves as a therapeutic target in hepatocellular carcinoma.