Using a method that combines genomics and systems biology, CDKN2A is identified as a possible indicator of survival in liver cancer

[Abstract] Objective The prognostic implications of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) are still uncertain, as cuproptosis is a recently discovered programmed cell death mechanism in tumors. Methods CRGs from TCGA were obtained and then screened based on their strong correlation with the expression matrix of lncRNA associated with cuproptosis in patients with HCC. LASSO-COX regression models were developed using data from the cancer genome atlas (TCGA) and the international cancer genome consortium (ICGC) databases to discover a prognostic signature related to cuproptosis. The models' accuracy was evaluated using Kaplan-Meier curves and ROC models. The prognostic signature related to cuproptosis was evaluated for its ability to predict outcomes in HCC through various survival models including OS, PFS, DFS, and DSS. To further investigate the prognostic signature related to cuproptosis in hepatoma cell lines, quantitative real-time PCR (qRT-PCR) and western blot techniques were utilized. It was then preceded by studying the proliferation, migration, and invasion through CCK-8 and transwell assays, while flow cytometry was used for studying apoptosis. The tumorigenesis in hepatoma cell lines concerning a cuproptosis-related prognostic signature was further studied using the lentivirus transfection method and a subcutaneous transplantation model. Results The study results indicated that CDKN2A was the crucial prognostic signature for HCC, in addition to highly expressed mRNA and proteins in hepatoma cell lines. The CDKN2A was determined as an independent variable distinguishing it from other HCC clinical features. CDKN2A knockdown not only inhibited the proliferation, migration, and invasion of hepatoma cell lines, but also arrested cell growth in the G2/M phase and promoted cell apoptosis. It precluded the growth of subcutaneous tumors in naked mice. Conclusion In this study, three original prognostic models for HCC were established based on identifying a cuproptosis-related prognostic signature, validated using cell assays and nude mice subcutaneous transplantation models. Thus, CDKN2A could potentially become a new target for treating HCC, providing a theoretical basis and recommendations for utilizing CRG targets in HCC therapy.