Identification of a Ferroptosis-Related Signature Model Including mRNAs and lncRNAs for Predicting Prognosis and Immune Activity in Hepatocellular Carcinoma

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.

Construction and Validation of a Ferroptosis-Related lncRNA Signature as a Novel Biomarker for Prognosis, Immunotherapy and Targeted Therapy in Hepatocellular Carcinoma

“…Statistical analysis showed that this risk model has good robustness and predictive power and that it can independently predict OS in patients with HCC. Furthermore, the predictive accuracy of our signature surpassed that of the previously reported prediction signature of HCC dependent on FR-lncRNAs or FRGs (Liang et al, 2020;Chen et al, 2021;Liang Wang et al, 2021;Liang et al, 2021;Nie et al, 2021;Wan et al, 2021;Xu et al, 2021). The nomogram consisting of age, stage, and six FR-related lncRNA risk scores could be used to visually predict the OS of individual patients with HCC at 1, 3, and 5 years.…”

Development and Validation of a Ferroptosis-Related lncRNAs Prognosis Model in Oral Squamous Cell Carcinoma

“…Morever, many lncRNAs are involved in the progression of malignant tumors and tumor resistance, and have become new biomarkers and therapeutic targets in cancer diagnosis and treatment ( Wang et al, 2019a ). The excellent predictive ability of frlncRNAs in cancer has been confirmed in a variety of cancers ( Chen et al, 2021b ; Lu et al, 2021 ; Jin et al, 2021 ; Li et al, 2021 ). However, the mechanism of frlncRNAs in OSCC is still unclear.…”

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

“…Zi-An Chen et al developed a predictive and prognostic ferroptosis-related signature model based on 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) in HCC [ 116 ]. The findings revealed differences of tumor microenvironment and immune cell infiltration as well as tumor-related pathways between low- and high-risk groups according to the established ferroptosis-related signature model in HCC.…”

“…Another approach is based on the interaction of ferroptosis and either long noncoding RNAs (lncRNAs) or miRNA as identified via in silico [ 116 , 117 , 124 ] or via in vitro/in vivo analyses [ 125 ].…”

“…As mentioned before, Zi-An Chen et al could develop a Ferroptosis-related signature predictive and prognostic model based on 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) in HCC [ 116 ].…”