Abstract
Purpose
Necroptosis plays an essential role in oncogenesis and tumor progression in hepatocellular carcinoma (HCC). This study aimed to investigate the role of necroptosis in the development and progression of HCC. Specifically, we constructed a prognostic prediction model using necroptosis-associated genes (NAGs) to predict patient outcomes.
Methods
Using data from The Cancer Genome Atlas (TCGA) database, we analyzed gene expression and clinical data. We identified a 5-gene model associated with NAGs and explored genetic features and immune cell infiltration using the CIBERSORT algorithm. In addition, we conducted single-cell RNA sequencing to investigate the potential role of necroptosis in HCC.
Results
We constructed a 5-gene prognostic model based on NAGs that demonstrated excellent predictive accuracy in both training and validation sets. Using multifactorial cox regression analysis, we confirmed the risk score derived from the model as an independent predictor of prognosis, surpassing other clinical characteristics. Patients with high risk scores had significantly worse prognosis than those with low risk scores. To enhance the clinical utility of the necroptosis score, we constructed an accurate nomogram. Additionally, we compared metabolic pathway and immune microenvironment differences between HCC tumors with high and low risk scores. Our single-cell RNA sequencing analyses revealed that necroptosis in HCC was primarily associated with a specific subset of macrophages.
Conclusions
Our study revealed the presence of two distinct necroptosis subtypes in HCC and developed a robust prognostic model with exceptional predictive accuracy. We observed significantly higher infiltration of M0 macrophages in the high-risk group. We propose that rescuing cytochrome c metabolism in HCC could serve as a potential therapeutic strategy. Furthermore, at a single-cell resolution, our analysis identified myeloid cells as the primary cells exhibiting necroptosis. Specifically, macrophages expressing CD5L, CETP, and MARCO, which may belong to a subset of tissue-resident macrophages, were found to be highly susceptible to necroptosis. These findings suggest the involvement of this specific macrophage subset in potential antitumor therapies. Our study provides novel insights into predicting patient prognosis and developing personalized therapeutic approaches for HCC.
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Data availability
The TCGA-LIHC dataset generated during the current study are available in the UCSC Xena (https://xena.ucsc.edu). The ScRNA-seq datasets generated during the current study are available in the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149614).
Abbreviations
- single-cell RNA seq:
-
Single-cell RNA sequencing
- bulk RNA seq:
-
Bulk RNA sequencing
- HCC:
-
Hepatocellular carcinoma
- iCCA/ICC:
-
Intrahepatic cholangiocarcinoma
- NAGs:
-
Necroptosis associated genes
- TCGA:
-
The Cancer Genome Atlas
- LASSO:
-
Least absolute shrinkage and selection operator
- AIC:
-
Akaike information criterion
- GSEA:
-
Gene Set Enrichment Analysis
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
- KM:
-
Kaplan–Meier
- PCA:
-
Principal Components Analysis
- ROC:
-
Receiver Operating Characteristic curve
- AUC:
-
Area under curve
- NES:
-
Normalized Enrichment Score
- OS:
-
Overall survival
- DEGs:
-
Differential expression genes
- TRMs:
-
Tissue-resident macrophages
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Acknowledgements
We thank all the team members for their hard work and efforts.
Funding
This study was supported by Shenzhen Science and Technology Program (Grant No. JSGG20201102162802008) and Key clinical research projects of Peking University Shenzhen Hospital (LCYJZD2021007).
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CJ was the study’s designer and director and wrote the manuscript. WC designed the study, carried out the bioinformatics analysis and data generation, and wrote the initial manuscript. TL and CC contributed to writing, reviewing, editing, and obtaining funding. CY conducted the literature collection. All authors read and approved the final manuscript.
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Chen, J., Chen, C., Tao, L. et al. A comprehensive analysis of the potential role of necroptosis in hepatocellular carcinoma using single-cell RNA Seq and bulk RNA Seq. J Cancer Res Clin Oncol 149, 13841–13853 (2023). https://doi.org/10.1007/s00432-023-05208-w
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DOI: https://doi.org/10.1007/s00432-023-05208-w