Abstract
BackgroundIn this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC.MethodsIntegrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes.ResultsFour genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The diagnostic models successfully distinguished HCC from normal samples and proliferative nodule samples. Compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression, and it was showed to affect Th17 cell differentiation and IL-17 signaling pathway through bioinformatics analysis, indicating it a potential agent of cancer immunotherapy.ConclusionsThe prognostic and diagnostic models based on the four genes indicated superior diagnostic and predictive performance, indicating new possibilities for individualized treatment of HCC patients.6i5hPu8DcyHvJLmULV1p7nVideo Graphical abstract
Highlights
In this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in hepatocellular carcinoma (HCC)
Identification of Differentially expressed gene (DEG) related to ferroptosis and iron metabolism in HCC A total of 104 ferroptosis- and iron metabolism-related genes were identified to match the mRNA-sequencing data in the The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases
Using limma with an absolute log2-fold change (FC) > 1 and an adjusted P value < 0.05 to perform differential expression analysis, we identified 24 DEGs (17 upregulated and 7 downregulated) in TCGA (Fig. 1a and c) and 16 DEGs (13 upregulated and 3 downregulated) in ICGC (Fig. 1b and d) that were related to ferroptosis and iron metabolism in HCC
Summary
We comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC. As the most frequent primary malignant tumor of the liver [1], hepatocellular carcinoma (HCC) is ranked as the sixth most commonly diagnosed neoplasm and is estimated to be the fourth leading cause of cancer-related death worldwide [2]. Based on multiple staging systems, HCC has made great progress in diagnosis and treatment, but most HCC staging systems are currently based on tumor burden and stratification of the disease by prognosis [4]. These systems lack sensitivity and have difficulty explaining the adverse biological characteristics that affect treatment and survival response, which generally limits the treatment effect for patients [5]. A better understanding of the molecular changes, molecular mechanisms and characterization involved in tumorigenesis and the identification of novel biomarkers that can individually predict the diagnosis and prognosis of tumors are essential for personalized medicine [7]
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