Abstract
BackgroundFerroptosis is a novel form of regulated cell death involved in tumor progression. The role of ferroptosis-related lncRNAs in hepatocellular carcinoma (HCC) remains unclear.MethodsRNA-seq and clinical data for HCC patients were downloaded from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) portal. Bioinformatics methods, including weighted gene coexpression network analysis (WGCNA), Cox regression, and least absolute shrinkage and selection operator (LASSO) analysis, were used to identify signature markers for diagnosis/prognosis. The tumor microenvironment, immune infiltration and functional enrichment were compared between the low-risk and high-risk groups. Subsequently, small molecule drugs targeting ferroptosis-related signature components were predicted via the L1000FWD and PubChem databases.ResultsThe prognostic model consisted of 2 ferroptosis-related mRNAs (SLC1A5 and SLC7A11) and 8 ferroptosis-related lncRNAs (AC245297.3, MYLK-AS1, NRAV, SREBF2-AS1, AL031985.3, ZFPM2-AS1, AC015908.3, MSC-AS1). The areas under the curves (AUCs) were 0.830 and 0.806 in the training and test groups, respectively. Decision curve analysis (DCA) revealed that the ferroptosis-related signature performed better than all pathological characteristics. Multivariate Cox regression analysis showed that the risk score was an independent prognostic factor. The survival probability of low- and high-risk patients could be clearly distinguished by the principal component analysis (PCA) plot. The risk score divided HCC patients into two distinct groups in terms of immune status, especially checkpoint gene expression, which was further supported by the Gene Ontology (GO) biological process, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, several small molecule drugs (SIB-1893, geldanamycin and PD-184352, etc) targeting ferroptosis-related signature components were identified for future reference.ConclusionWe constructed a new ferroptosis-related mRNA/lncRNA signature for HCC patients. The model can be used for prognostic prediction and immune evaluation, providing a reference for immunotherapies and targeted therapies.
Highlights
According to epidemiological studies, hepatocellular carcinoma (HCC) is considered the seventh most common malignancy and the second most common cause of cancer-related death [1]
We evaluated the predictive value of the ferroptosis-related signature and investigated the differential immune response in a variety of ways, including tumor microenvironment (TME) analysis and single-sample gene set enrichment analysis
The RNA sequencing and clinical data of HCC patients were downloaded from the The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) portal on April 30, 2021
Summary
Hepatocellular carcinoma (HCC) is considered the seventh most common malignancy and the second most common cause of cancer-related death [1]. The detailed mechanism underlying the role of ferroptosis in tumors is still unclear, several studies have reported that ferroptosis is involved in various cancers, including breast cancer [4,5,6], pancreatic cancer [7], ovarian cancer [8], and HCC [9,10,11,12]. In addition to ferroptosis-inducing agents, an increasing number of ferroptosis-related genes have been identified and found to be involved in the progression of cancers by serving as mediators of ferroptosis-related pathways. In HCC, CISD1 and a polymorphism of the TP53 gene (the S47 variant) are reported to negatively regulate ferroptosis, which proves that ferroptosis-related genes play a role in tumor progression [17, 18]. Ferroptosis is a novel form of regulated cell death involved in tumor progression. The role of ferroptosis-related lncRNAs in hepatocellular carcinoma (HCC) remains unclear
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