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

Yan Ye,1 Yanmei Zeng,1 Shenggang Huang,1,2 Chunping Zhu,1,2 Qingshui Wang3 1Ganzhou Key Laboratory of Molecular Medicine, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of China; 3College of Integrative Medicine, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of ChinaCorrespondence: Chunping Zhu; Qingshui Wang, Email [email protected]; [email protected]: 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. Keywords: hepatocellular carcinoma, chemotherapy, DNAJC8, sorafenib, IC50