Association Analysis of CPSF4-PRKDC Co-expression with Poor Prognosis, Immune Microenvironment Characteristics, and Sorafenib Sensitivity in Hepatocellular Carcinoma

Abstract This study elucidates the synergistic oncogenic effects and clinical translational significance of Cleavage and Polyadenylation Specific Factor 4 (CPSF4) and the DNA repair kinase PRKDC in hepatocellular carcinoma (HCC). An analysis of the TCGA cohort revealed a significant positive correlation between CPSF4 and PRKDC expression in HCC (r = 0.31, P < 0.001), with patients exhibiting high expression levels of both genes experiencing notably reduced overall survival (HR = 2.202, P = 0.002). The risk score model, based on these two genes, demonstrated area under the curve (AUC) values of 0.703, 0.631, and 0.611 at 1, 2, and 3 years in the TCGA training dataset, and AUC values of 0.684, 0.736, and 0.757 at 1, 2, and 3 years in the ICGC validation dataset, indicating stable prognostic predictive capability. Further analysis identified a strong association between elevated expression of both genes and characteristics of an immunosuppressive tumor microenvironment. Functional experiments substantiated that simultaneous knockdown of CPSF4 and PRKDC synergistically inhibited malignant phenotypes of HCC cells, significantly curtailing cell proliferation, migration, and invasion capabilities while enhancing sensitivity to sorafenib. The synergistic interaction between CPSF4 and PRKDC presents a viable prognostic marker and potential therapeutic target for HCC, with implications for modulating sorafenib responsiveness, thereby offering novel insights for clinical application.