Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.
Front Immunol. 2021 Sep 17;12:719175. doi: 10.3389/fimmu.2021.719175. eCollection 2021.
Ferroptosis is an iron-dependent cell death process that plays important regulatory roles in the occurrence and development of cancers, including hepatocellular carcinoma (HCC). Moreover, the molecular events surrounding aberrantly expressed long non-coding RNAs (lncRNAs) that drive HCC initiation and progression have attracted increasing attention. However, research on ferroptosis-related lncRNA prognostic signature in patients with HCC is still lacking. In this study, the association between differentially expressed lncRNAs and ferroptosis-related genes, in 374 HCC and 50 normal hepatic samples obtained from The Cancer Genome Atlas (TCGA), was evaluated using Pearson's test, thereby identifying 24 ferroptosis-related differentially expressed lncRNAs. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression model were used to construct and validate a prognostic risk score model from both TCGA training dataset and GEO testing dataset (GSE40144). A nine-lncRNA-based signature (CTD-2033A16.3, CTD-2116N20.1, CTD-2510F5.4, DDX11-AS1, LINC00942, LINC01224, LINC01231, LINC01508, and ZFPM2-AS1) was identified as the ferroptosis-related prognostic model for HCC, independent of multiple clinicopathological parameters. In addition, the HCC patients were divided into high-risk and low-risk groups according to the nine-lncRNA prognostic signature. The gene set enrichment analysis enrichment analysis revealed that the lncRNA-based signature might regulate the HCC immune microenvironment by interfering with tumor necrosis factor α/nuclear factor kappa-B, interleukin 2/signal transducers and activators of transcription 5, and cytokine/cytokine receptor signaling pathways. The infiltrating immune cell subtypes, such as resting memory CD4(+) T cells, follicular helper T cells, regulatory T cells, and M0 macrophages, were all significantly different between the high-risk group and the low-risk group as indicated in Spearman's correlation analysis. Moreover, a substantial increase in the expression of B7H3 immune checkpoint molecule was found in the high-risk group. Our findings provided a promising insight into ferroptosis-related lncRNAs in HCC and a personalized prediction tool for prognosis and immune responses in patients.
铁死亡是一种依赖铁的细胞死亡过程，在包括肝细胞癌（HCC）在内的癌症的发生和发展中起着重要的调节作用。此外，异常表达的长链非编码 RNA（lncRNA）驱动 HCC 发生和进展的分子事件越来越受到关注。然而，关于 HCC 患者铁死亡相关 lncRNA 预后特征的研究仍然缺乏。在这项研究中，通过 Pearson 检验评估了 374 例 HCC 患者和 50 例来自癌症基因组图谱（TCGA）的正常肝组织样本中差异表达的 lncRNA 与铁死亡相关基因之间的关联，从而鉴定出 24 个铁死亡相关差异表达的 lncRNA。最小绝对收缩和选择算子（LASSO）算法和 Cox 回归模型用于从 TCGA 训练数据集和 GEO 测试数据集（GSE40144）构建和验证预后风险评分模型。基于 9 个 lncRNA 的特征（CTD-2033A16.3、CTD-2116N20.1、CTD-2510F5.4、DDX11-AS1、LINC00942、LINC01224、LINC01231、LINC01508 和 ZFPM2-AS1）被确定为 HCC 的铁死亡相关预后模型，独立于多种临床病理参数。此外，根据这 9 个 lncRNA 预后特征，将 HCC 患者分为高风险组和低风险组。基因集富集分析富集分析表明，该 lncRNA 特征可能通过干扰肿瘤坏死因子α/核因子 kappa-B、白细胞介素 2/信号转导和转录 5 以及细胞因子/细胞因子受体信号通路来调节 HCC 免疫微环境。Spearman 相关性分析表明，高风险组和低风险组之间的浸润免疫细胞亚型（如静止记忆 CD4(+) T 细胞、滤泡辅助 T 细胞、调节 T 细胞和 M0 巨噬细胞）存在显著差异。此外，在高风险组中发现 B7H3 免疫检查点分子的表达显著增加。我们的研究结果为 HCC 中铁死亡相关 lncRNA 提供了有前景的见解，并为患者的预后和免疫反应提供了个性化的预测工具。
