背景:角化是一种新的细胞死亡形式,与线粒体呼吸密切相关,与先前表征的细胞死亡形式相比,它通过不同的机制发生。然而,角化相关基因(CAGs)对预后的确切影响,免疫谱,肝细胞癌(HCC)的治疗效果仍然知之甚少。
方法:使用HCC患者的基因组数据对肝细胞癌(HCC)预后中的CAGs进行了综合分析。进行共识聚类分析以确定与HCC中的角化相关的分子亚型。应用单样本基因集富集分析(ssGSEA)算法对免疫细胞浸润水平进行量化,而“估计”包用于计算肿瘤纯度,基质分数,和肿瘤微环境(TME)中的免疫评分。利用主成分分析(PCA)算法构建与CAG相关的风险评分。最后,CCK8,伤口愈合,Transwell迁移/入侵,使用EDU和异种移植模型来探索MTF1的潜在致癌作用。
结果:确定了三种不同的角化修饰模式,每个都与独特的功能丰富相关,临床特征,免疫细胞浸润,免疫检查点,肿瘤微环境(TME),和预后。开发了CAGs相关风险评分(Cuscore)来预测TCGA的预后,并在GSE76427和ICGC数据集中进行了验证。值得注意的是,低Cuscore患者的预后更好,更有可能从免疫治疗中获益.此外,HCC中的高Cuscore组还揭示了三个潜在的治疗靶标(TUBA1B,CDC25B,和CSNK2A1)以及几种治疗性化合物。此外,实验测量了6种预后相关的CAGs的表达水平,其中MTF1的敲低表现出增殖的抑制,入侵,和肝癌细胞系中的迁移形成。
结论:这些发现增强了我们对HCC的角化特征的理解,基于CuScore的分层可能会增强对患者预后的预测,并促进有效和创新治疗策略的开发。
Cuproptosis is a novel form of cell death that exhibits close association with mitochondrial respiration and occurs through distinct mechanisms compared to previously characterized forms of cell death. However, the precise impact of cuproptosis-associated genes (CAGs) on prognosis, immune profiles, and treatment efficacy in hepatocellular carcinomas (HCC) remains poorly understood.
A comprehensive analysis of CAGs in hepatocellular carcinoma (HCC) prognosis was conducted using genomic data from HCC patients. Consensus clustering analysis was performed to determine molecular subtypes related to cuproptosis in HCC. The single-sample gene set enrichment analysis (ssGSEA) algorithm was applied to quantify the infiltration levels of immune cells, while the \"ESTIMATE\" package was employed to calculate tumor purity, stromal scores, and immune scores in the tumor microenvironment (TME). Principal component analysis (PCA) algorithm was utilized to construct a risk score related to CAGs. Finally, CCK8, wound healing, Transwell migration/invasion, EDU and xenograft model were employed to explore the potential oncogenic role of MTF1.
Three distinct patterns of cuproptosis modification were identified, each associated with unique functional enrichments, clinical characteristics, immune cell infiltration, immune checkpoints, tumor microenvironment (TME), and prognosis. A CAGs-related risk score (Cuscore) was developed to predict prognosis in TCGA and validated in GSE76427 and ICGC datasets. Notably, patients with a low Cuscore had better prognoses and were more likely to benefit from immunotherapy.Additionally, the high Cuscore group in HCC also revealed three potential therapeutic targets (TUBA1B, CDC25B, and CSNK2A1) as well as several therapeutic compounds. Moreover, the experiment measured the expression levels of six prognosis-related CAGs, wherein knockdown of MTF1 exhibited suppression of proliferation, invasion, and migration formation in HCC cell lines.
The findings have enhanced our comprehension of the cuproptosis characteristics in HCC, and stratification based on CuScore may potentially enhance the prediction of patients\' prognosis and facilitate the development of effective and innovative treatment strategies.