背景:肝细胞癌(HCC),令人沮丧的发病率和死亡率,是世界上最常见的肿瘤之一。嘧啶代谢是调节细胞中DNA和RNA合成的关键过程。探讨嘧啶代谢在肝癌中的意义势在必行。
方法:从TCGA数据库和GEO数据库下载转录组和临床数据。与嘧啶代谢相关的基因来源于MSigDB。通过Cox回归和Lasso回归构建嘧啶代谢相关特征(PMRS),然后在ICGC数据库的外部验证集中进行验证。功能富集,免疫浸润分析,药物敏感性,和Immunphenoscore(IPS)进一步实施以预测对免疫疗法的反应。通过进行一系列体外实验,探讨了PMRS在肝细胞癌恶性表型中的作用。
结果:我们的研究开发了四基因PMRS,这表明与HCC患者的预后具有实质性的相关性。作为临床实践中的独立预测因子。风险分层分析的结果提供了证据,表明低风险患者经历了更有利的临床结局。列线图显示出显著的预后预测价值。随后的结果表明,低风险患者对免疫疗法表现出更有希望的反应。此外,细胞实验结果表明,DCK的下调明显抑制了肝细胞癌的恶性表型。
结论:我们以嘧啶代谢为中心的预后特征能准确预测总生存期,免疫状态,和肝细胞癌(HCC)患者的治疗反应,提供精确诊断的创新见解,个性化治疗,改善预后。
Hepatocellular carcinoma (HCC), with discouraging morbidity and mortality, ranks as one of the most prevalent tumors worldwide. Pyrimidine metabolism is a critical process that regulates DNA and RNA synthesis in cells. It is imperative to investigate the significance of pyrimidine metabolism in liver cancer.
Transcriptome and clinical data were downloaded from the TCGA database and the GEO database. The genes related to pyrimidine metabolism were sourced from the MSigDB. The pyrimidine metabolism-related signature (PMRS) was constructed through Cox regression and Lasso regression and then verified in the external validation set from the ICGC database. Functional enrichment, immune infiltration analysis, drug sensitivity, and Immunophenoscore (IPS) were further implemented to predict the response to immunotherapy. The role of PMRS in the malignant phenotype of hepatocellular carcinoma was explored by conducting a series of in vitro experiments.
Our study developed a four-genes PMRS which demonstrates a substantial correlation with the prognosis of HCC patients, serving as an independent predictor in clinical practice. The result of risk-stratified analysis yielded evidence that low-risk patients experienced more favorable clinical outcomes. The nomogram exhibited remarkable prognostic predictive value. The subsequent results revealed that low-risk patients manifested a more promising response to immunotherapy. Moreover, the results of cell experiments demonstrated that the downregulation of DCK markedly inhibited the malignant phenotype of hepatocellular carcinoma.
Our pyrimidine metabolism-centered prognostic signature accurately predicts overall survival, immune status, and treatment response in hepatocellular carcinoma (HCC) patients, offering innovative insights for precise diagnosis, personalized treatment, and improved prognosis.