Single-cell transcriptomics reveals over-activated reactive oxygen species pathway in hepatocytes in the development of hepatocellular carcinoma.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Carcinoma, Hepatocellular*/genetics ; Carcinoma, Hepatocellular*/metabolism ; Carcinoma, Hepatocellular*/pathology ; Liver Neoplasms*/genetics ; Liver Neoplasms*/metabolism ; Liver Neoplasms*/pathology ; Reactive Oxygen Species*/metabolism ; Hepatocytes*/metabolism ; Hepatocytes*/pathology ; Single-Cell Analysis* ; Gene Expression Regulation, Neoplastic* ; Transcriptome*; Humans ; Gene Expression Profiling ; Gene Regulatory Networks

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor and a primary cause of cancer-relevant deaths worldwide. The role of reactive oxygen species (ROS) in HCC development is less studied.
Methods: Seurat package and CellMarker database were employed for single-cell RNA sequencing (scRNA-seq) analysis based on the GSE189175 dataset from Gene Expression Omnibus (GEO). DAVID and MsigDB database were utilized for pathway analysis. SCENIC analysis was performed to map a transcription factors (TFs) regulatory network. CellChat was used for cellular communication analysis.
Results: Six major cell subpopulations were identified, among which hepatocytes accounted for the highest proportion in both cancer and adjacent tissues. The enrichment scores of the 50 hallmark gene sets showed that the ROS pathway was abnormally activated in HCC hepatocytes and positively correlated with energy metabolism-related pathways (glucose metabolism, lipid metabolism, amino acid metabolism, etc.). Then, the hepatocytes were divided into four subgroups. Noticeably, GPX4+  hepatocytes with the highest activity of the ROS pathway was related to a worse prognosis of HCC. Mechanism analysis revealed that JUND was involved in the positive regulation of the ROS pathway in GPX4+  hepatocytes. It was found that the interdependent ligand-receptor interaction between GPX4+  liver cells and immune cells facilitated the malignant development of HCC.
Conclusion: ROS pathway was over-activated in the hepatocytes of HCC tissues. GPX4+  hepatocytes having the highest activity of the ROS pathway closely interacted with T cells and M2 macrophage cells. Molecular subtypes and risk score signature based on the ROS pathway and its potential target gene JUND are encouraged to be developed for improving the precision treatment of HCC.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)

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Keywords: CellChat; GPX4+  HCC hepatocytes; Hepatocellular carcinoma; Reactive oxygen species pathway; Single-cell transcriptomics

0 (Reactive Oxygen Species)

Date Created: 20241130 Date Completed: 20241130 Latest Revision: 20241204

20241204

PMC11608336

10.1038/s41598-024-81481-0

39616235