Dataset Information

Prognostic Role and Potential Mechanisms of the Ferroptosis-Related Metabolic Gene Signature in Hepatocellular Carcinoma.

ABSTRACT:

Purpose

Ferroptosis, as a novel regulated cell death form, has a close interaction with metabolism, which is largely unknown in cancer. In the present study, we conducted a comprehensive analysis of ferroptosis-related metabolic genes to delineate the metabolic signatures induced by ferroptosis and evaluate its prognostic significance in hepatocellular carcinoma (HCC).

Methods

The ferroptosis-related metabolic genes (Fer-MRGs) were identified by correlation analyses with transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Then, univariate and the least absolute shrinkage and selection operator Cox regression analysis was used to establish a novel risk score model. Univariate and multivariate COX analyses were used to identify independent prognostic factors for overall survival (OS) of HCC, and a nomogram was developed. The Fer-MRGs' expression was further evaluated by quantitative real-time polymerase chain reaction in HCC.

Results

A total of 77 metabolic genes were identified as Fer-MRGs, and 26 were found with prognostic values for OS of HCC. Then, a novel nine-gene (AKR1C3, ATIC, G6PD, GMPS, GNPDA1, IMPDH1, PRIM1, RRM2, and TXNRD1) risk score model was constructed. Survival analyses showed worse OS in high-risk patients both in the training and validation groups. The model was also identified as an independent prognostic factor for HCC, and a prognostic nomogram for OS was further established with superior discriminative capacity and prediction accuracy. Notably, close correlations were also identified between the risk score and the expression of immune checkpoint genes, immune subtypes of tumor, and susceptibility of HCC to chemotherapeutic agents. Finally, elevated expression of eight Fer-MRGs (except for IMPDH1) was further verified in 16 pairs of HCC tumor and adjacent tissues.

Conclusion

These results indicated the intense interaction between ferroptosis and metabolism, the significant role of ferroptosis-related MRGs, and the great potential of the novel risk score model for prognosis prediction in HCC.

SUBMITTER: Dai T

PROVIDER: S-EPMC8349220 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background: Immune checkpoint blockers (ICBs) are increasingly being used to treat patients with advanced hepatocellular carcinoma (HCC), but only a third of these patients are sensitive to ICBs. Emerging evidence suggests that ferroptosis could be a novel target for antitumor treatment, and combined treatment with ferroptosis inducers might enhance sensitivity to immunotherapy. However, there is a lack of information on the crosstalk between ferroptosis-related lncRNAs and anti-tumor immunity. Therefore, we aim to explore prognostic value of ferroptosis-related lncRNAs and clarify potential role in ICBs of HCC. Methods: We obtained mRNA and lncRNA expression data from two independent cohorts (TCGA and GEO database). Univariate Cox, the least absolute shrinkage and selection operator (Lasso) algorithm and multivariate Cox analysis were used to construct a lncRNA signature, which was evaluated using the area under the receiver operating characteristic curve (AUC) and Kaplan-Meier curves. Tumor-infiltrating cell (TIC) profiling and the tumor immune dysfunction and exclusion (TIDE) algorithm were used to validate the signature model and immunotherapy. Finally, we adopted RT-PCR assay to evaluate the differential expression of lncRNAs in HCC tissues in our hospital. Results: The ferroptosis-related lncRNA signature included five lncRNAs, most of which were positively correlated with clinical stage and grade. The signature could stratify patients into two risk groups, with the high-risk group associated with a shorter overall survival (OS, p < 0.05) in TCGA-LIHC and GSE76427. Besides, the AUCs of the 1-, 3-, and 5-years OS were 0.772, 0.707, and 0.666, respectively. Gene set enrichment analysis (GESA) of lncRNAs revealed enrichment of oncogenic and immune-related pathways. The TIC profiling indicated a close correlation between the signature and immune cells. Furthermore, the high-risk group had a better response to immunotherapy than low-risk group. RT-PCR demonstrated these five lncRNAs were upregulated in cancerous tissue than normal tissues. Conclusions: The ferroptosis-related lncRNA signature could accurately predict the OS of HCC patients and may serve as an independent clinical factor for patients' outcomes. Ferroptosis-related lncRNAs may remodel the tumor microenvironment (TME) and affect the anti-cancer ability of ICBs, and therefore, could potentially act as an indicator for the response to immunotherapy in HCC.

Project description:Background: Ferroptosis, as a unique programmed cell death modality, has been found to be closely related to the occurrence and development of hepatocellular carcinoma (HCC). Hypoxia signaling pathway has been found to be extensively involved in the transformation and growth of HCC and to inhibit anti-tumor therapy through various approaches. However, there is no high-throughput study to explore the potential link between ferroptosis and hypoxia, as well as their combined effect on the prognosis of HCC. Methods: We included 370 patients in The Cancer Genome Atlas (TCGA) database and 231 patients in the International Cancer Genome Consortium (ICGC) database. Univariate COX regression and Least Absolute Shrinkage and Selection Operator approach were used to construct ferroptosis-related genes (FRGs) and hypoxia-related genes (HRGs) prognostic signature (FHPS). Kaplan-Meier method and Receiver Operating Characteristic curves were analyzed to evaluate the predictive capability of FHPS. CIBERSOR and single-sample Gene Set Enrichment Analysis were used to explore the connection between FHPS and tumor immune microenvironment. Immunohistochemical staining was used to compare the protein expression of prognostic FRGs and HRGs between normal liver tissue and HCC tissue. In addition, the nomogram was established to facilitate the clinical application of FHPS. Results: Ten FRGs and HRGs were used to establish the FHPS. We found consistent results in the TCGA training cohort, as well as in the independent ICGC validation cohort, that patients in the high-FHPS subgroup had advanced tumor staging, shorter survival time, and higher mortality. Moreover, patients in the high-FHPS subgroup showed ferroptosis suppressive, high hypoxia, and immunosuppression status. Finally, the nomogram showed a strong prognostic capability to predict overall survival (OS) for HCC patients. Conclusion: We developed a novel prognostic signature combining ferroptosis and hypoxia to predict OS, ferroptosis, hypoxia, and immune status, which provides a new idea for individualized treatment of HCC patients.