Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
J Cell Mol Med. 2024 Oct;28(20):e70083. doi: 10.1111/jcmm.70083.
Hepatocellular carcinoma (HCC) stands as the most prevalent and treatment-resistant malignant tumour, characterized by a dismal prognosis. Croton acylation (CA) has recently gained attention as a critical factor in cancer pathogenesis. This study sought to rapidly identify prognostic features of HCC linked to CA. Differential analysis was conducted between tumour tissues and adjacent non-tumour tissues in the TCGA-LIHC and GSE76427 datasets to uncover differentially expressed genes (DEG1 and DEG2). The intersection of DEG1 and DEG2 highlighted DEGs with consistent expression patterns. Single-sample gene set enrichment analysis scores were calculated for 18 lysine crotonylation-related genes (LCRGs) identified in prior research, showing significant differences between tumour and normal groups. Subsequently, weighted gene co-expression network analysis was employed to identify key module genes correlated with the LCRG score. Candidate genes were identified by overlapping consistently expressed DEGs with key module genes. Prognostic features were identified, and risk scores were determined via regression analysis. Patients were categorized into risk groups based on the optimal cutoff value. Gene set enrichment analysis (GSEA) and immunoassays were also performed. The prognostic features were further validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A total of 88 candidate genes were identified from 1179 consistently expressed DEGs and 4200 key module genes. Seven prognostic features were subsequently identified: TMCO3, RAP2A, ITGAV, ZFYVE26, CHST9, HMGN4, and KLHL21. GSEA revealed that DEGs between risk groups were primarily associated with chylomicron metabolism, among other pathways. Additionally, activated CD4+ T cells demonstrated the strongest positive correlation with risk scores, and most immune checkpoints showed significant differences between risk groups, with ASXL1 exhibiting the strongest correlation with risk scores. The Tumour Immune Dysfunction and Exclusion score was notably higher in the high-risk group. Moreover, in both the TCGA-LIHC and ICGC-LIRI-JP datasets, the expression of other prognostic features was elevated in tumour tissues, with the exception of CHST9. RT-qPCR confirmed the increased expression of TMCO3, RAP2A, ITGAV, ZFYVE26, and HMGN4. This study establishes a risk model for HCC based on seven crotonylation-associated prognostic features, offering a theoretical framework for the diagnosis and treatment of HCC.
肝细胞癌（HCC）是最常见和最难治疗的恶性肿瘤，预后不良。最近，巴豆酰化（CA）被认为是癌症发病机制中的一个关键因素。本研究旨在快速鉴定与 CA 相关的 HCC 预后特征。在 TCGA-LIHC 和 GSE76427 数据集的肿瘤组织和相邻非肿瘤组织之间进行差异分析，以发现差异表达基因（DEG1 和 DEG2）。DEG1 和 DEG2 的交集突出了具有一致表达模式的 DEG。对于先前研究中鉴定的 18 个赖氨酸巴豆酰化相关基因（LCRG），计算了单样本基因集富集分析评分，结果显示肿瘤组和正常组之间存在显著差异。随后，采用加权基因共表达网络分析鉴定与 LCRG 评分相关的关键模块基因。通过与关键模块基因重叠一致表达的 DEG 来鉴定候选基因。通过回归分析确定预后特征并确定风险评分。根据最佳截断值将患者分为风险组。还进行了基因集富集分析（GSEA）和免疫测定。通过逆转录定量聚合酶链反应（RT-qPCR）进一步验证预后特征。从 1179 个一致表达的 DEG 和 4200 个关键模块基因中鉴定出 88 个候选基因。随后确定了 7 个预后特征：TMCO3、RAP2A、ITGAV、ZFYVE26、CHST9、HMGN4 和 KLHL21。GSEA 表明，风险组之间的 DEG 主要与乳糜微粒代谢等途径相关。此外，激活的 CD4+T 细胞与风险评分呈最强正相关，大多数免疫检查点在风险组之间存在显著差异，其中 ASXL1 与风险评分的相关性最强。高风险组的肿瘤免疫功能障碍和排斥评分明显更高。此外，在 TCGA-LIHC 和 ICGC-LIRI-JP 数据集，除 CHST9 外，其他预后特征在肿瘤组织中的表达均升高。RT-qPCR 证实 TMCO3、RAP2A、ITGAV、ZFYVE26 和 HMGN4 的表达增加。本研究基于 7 个与巴豆酰化相关的预后特征建立了 HCC 风险模型，为 HCC 的诊断和治疗提供了理论框架。
