Integrative Analysis Identified an Eight-Gene Risk Signature Linked to CDK7 and Explored Its Association with HCC...

Backgrounds: Cyclin-dependent kinase 7 (CDK7) plays key roles in transcription and cell cycle regulation, and its inhibition has been proposed as a potential therapeutic strategy for hepatocellular carcinoma (HCC). The primary research objective of this study is to identify and validate CDK7-associated prognostic genes in HCC using bioinformatics approaches, construct a reliable prognostic risk model, and explore the functional role of CDK7 in HCC progression through in vitro and in vivo experiments, with a specific focus on its association with RelA/p65 phosphorylation, so as to provide evidence supporting CDK7 as a potential prognostic biomarker and therapeutic target for HCC. Methods: Two independent HCC cohorts from The Cancer Genome Atlas (TCGA)-HCC and the Gene Expression Omnibus (dataset GSE14520) were analyzed. Patients were stratified by CDK7 expression. Differentially expressed genes were identified in both CDK7-based and tumor-versus-normal comparisons, and the intersection of these genes was analyzed. Univariate Cox regression and machine learning were used to screen prognostic genes and construct a risk model. The model's predictive utility was assessed using Kaplan-Meier and receiver operating characteristic (ROC) analyses. Mutation landscapes were compared between risk groups. The functional association of CDK7 was validated through in vitro and in vivo experiments. Results: Eight prognostic genes (CHGA, SH2D5, ACTBP12, SOX2, AGR2, ISM2, KRT12, and BRDT) were screened from 98 intersecting genes via univariate Cox regression and least absolute shrinkage and selection operator regression analyses to construct a risk model. In the TCGA-HCC (374 HCC samples and 50 control samples) and GSE14520 cohorts (222 HCC samples and 212 control samples), patients in the high-risk group had significantly worse overall survival than those in the low-risk group (Hazard Ratio [HR] = 0.003-0.036, 95% Confidence Interval [CI] = 1.01-4.28, p < 0.05). The predictive accuracy of the model was moderate, with the areas under the ROC curves (AUCs) for 1-, 3-, and 5-year survival exceeding 0.6 (specifically, 0.69 for 3-year survival). In vitro and in vivo experiments demonstrated that CDK7 expression is associated with HCC proliferation, migration, invasion, and tumor growth, and this association might be related to RelA/p65 phosphorylation. Conclusions: This study identified a novel eight-gene prognostic signature linked to CDK7 in HCC and provided experimental evidence that CDK7 promotes tumor aggressiveness. These findings suggest the potential of CDK7 as a prognostic biomarker and therapeutic target for HCC, though further validation of its clinical utility is needed.