Ke Shaoying, Wang Congren, Su Zijian, Lin Shaoze, Wu Gongle
Hepatological Surgery Department, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, China.
Front Genet. 2022 May 16;13:897683. doi: 10.3389/fgene.2022.897683. eCollection 2022.
The carcinogenesis and prognosis of hepatocellular carcinoma (HCC) involve complex molecular mechanisms, and ferroptosis is related to the development and therapeutic efficacy of HCC, but the specific mechanism and prognostic role of ferroptosis-related genes in HCC have not been elucidated. Differentially expressed gene analysis, Cox regression, and unsupervised consensus clustering were applied to identify crucial ferroptosis regulators and establish ferroptosis-related subtypes in HCC. Random forest analysis and survival analysis were adopted to confirm FTL as the hub prognostic and diagnostic ferroptosis regulator in HCC. The ferroptosis-related subtypes based on the crucial prognostic ferroptosis regulators showed that patients in fescluster A had a higher survival probability ( < 0.001) and better clinical characteristics than patients in fescluster B in the TCGA-LIHC cohort. Patients with a high tumor mutation burden (TMB) in fescluster B presented a significantly poorer prognosis. FTL was the core ferroptosis regulator, and its low expression revealed a significant survival advantage compared with its high expression ( = 0.03). The expression and predictive value of FTL were both closely related to the clinical features ( < 0.05). Expression of FTL accurately distinguished HCC from normal tissues in the TCGA-LIHC cohort, ICGC cohort, and GSE14520 dataset. In addition, higher infiltrating fractions of immune cells, such as activated CD8 T cells and Gamma delta T cells, mainly enriched immune-related signaling pathways, including the IL2-STAT3 signaling pathway and interferon-gamma response signaling pathway, and higher expression of immune checkpoints, including PDCD1, CTLA4, TIGIT, and CD83, were presented in patients with high FTL expression ( < 0.05). Patients with high FTL were more sensitive to some targeted drugs, such as cisplatin, dasatinib, and sorafenib, than those with low FTL ( < 0.05). A nomogram based on FTL accurately predicted the prognosis of HCC. Further knockdown of FTL was determined to significantly inhibit cell proliferation and migration in HCC. Our study validated ferroptosis-related subtypes and FTL with effective prognostic value in HCC and was beneficial for identifying candidates suitable for targeted drug therapy and immunotherapy, thereby offering further insight into individual treatment strategies to improve disease outcomes in HCC patients.
肝细胞癌（HCC）的致癌作用和预后涉及复杂的分子机制，铁死亡与HCC的发生发展及治疗效果相关，但铁死亡相关基因在HCC中的具体机制和预后作用尚未阐明。应用差异表达基因分析、Cox回归和无监督一致性聚类来鉴定关键的铁死亡调节因子并在HCC中建立铁死亡相关亚型。采用随机森林分析和生存分析来确认FTL是HCC中关键的预后和诊断性铁死亡调节因子。基于关键预后性铁死亡调节因子的铁死亡相关亚型显示，在TCGA-LIHC队列中，fescluster A组患者的生存概率更高（<0.001），临床特征优于fescluster B组患者。fescluster B组中肿瘤突变负荷（TMB）高的患者预后明显较差。FTL是核心铁死亡调节因子，其低表达与高表达相比显示出显著的生存优势（=0.03）。FTL的表达和预测价值均与临床特征密切相关（<0.05）。在TCGA-LIHC队列、ICGC队列和GSE14520数据集中，FTL的表达能准确区分HCC与正常组织。此外，FTL高表达的患者中，活化CD8 T细胞和γδ T细胞等免疫细胞的浸润分数更高，主要富集免疫相关信号通路，包括IL2-STAT3信号通路和干扰素-γ反应信号通路，免疫检查点包括PDCD1、CTLA4、TIGIT和CD83的表达也更高（<0.05）。FTL高的患者比FTL低的患者对某些靶向药物，如顺铂、达沙替尼和索拉非尼，更敏感（<0.05）。基于FTL的列线图准确预测了HCC的预后。进一步敲低FTL可显著抑制HCC细胞的增殖和迁移。我们的研究验证了铁死亡相关亚型和具有有效预后价值的FTL在HCC中的作用，有助于识别适合靶向药物治疗和免疫治疗的候选者，从而为改善HCC患者疾病结局的个体化治疗策略提供进一步见解。
