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.
Highlights
Hepatocellular carcinoma (HCC) is a heterogeneous tumor with increased incidence in the world [1, 2]
We identified 3,714 genes (3,433 upregulated and 281 downregulated) that were differentially expressed in the TCGAHCC dataset (Figures 1A, B and Supplementary Table S3)
Ferroptosis has been reported to be involved in the development of HCC [25, 26], so we wanted to explore whether ferroptosis-related genes existed in the differentially expressed genes (DEGs)
Summary
Hepatocellular carcinoma (HCC) is a heterogeneous tumor with increased incidence in the world [1, 2]. The importance of ferroptosis has been demonstrated in the regulation of metabolism and redox biology, affecting the pathogenesis and treatment of cancers, including HCC. Shan and colleagues reported that ubiquitin-like modifier activating enzyme 1 promoted the development of HCC by upregulating the Nrf signaling pathway and downregulating Fe2+ levels, triggering ferroptosis inhibitory bioactivities [8]. Sorafenib and sulfasalazine could synergistically inhibit the activation of branched-chain amino acid aminotransferase 2, a key enzyme participating in sulfur amino acid metabolism, resulting in ferroptosis in HCC HepG2 cells in vitro and in vivo [9]. Liu et al reported a ferroptosis- and immune-related signature and found that this prognostic signature could be used to screen the HCC patients for immunotherapies and targeted therapies [10]. Understanding the underlying mechanisms and functions of ferroptosis-associated gene changes in HCC is of vital importance
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