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构建铁死亡相关的九个长链非编码 RNA 标志物用于预测肝细胞癌的预后和免疫反应。

Construction of a Ferroptosis-Related Nine-lncRNA Signature for Predicting Prognosis and Immune Response in Hepatocellular Carcinoma.

机构信息

Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.

Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.

出版信息

Front Immunol. 2021 Sep 17;12:719175. doi: 10.3389/fimmu.2021.719175. eCollection 2021.

Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/380f/8484522/116493ac1199/fimmu-12-719175-g001.jpg

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