Single-cell and genetic multi-omics analysis combined with experiments confirmed the signature and potential targets of cuproptosis in hepatocellular carcinoma

Frontiers in Cell and Developmental Biology

Cell and Developmental Biology

Wenyong Wu¹  Yong Qi¹  Feng Cao²  Xutong Li³  Chuang Yang⁴ 

[1] Department of General Surgery, The First Hospital of Anhui Medical University, Hefei, China;Department of General, Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany;Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China;Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany;

关键词: hepatocellular carcinoma;    cuproptosis;    programmed cell death;    immune microenvironment;    single-cell RNA-sequencing;    molecular docking;   

DOI  :  10.3389/fcell.2023.1240390

 received in 2023-06-14, accepted in 2023-08-24,  发布年份 2023

来源: Frontiers

【 摘 要 】

Background: Cuproptosis, as a recently discovered type of programmed cell death, occupies a very important role in hepatocellular carcinoma (HCC) and provides new methods for immunotherapy; however, the functions of cuproptosis in HCC are still unclear.Methods: We first analyzed the transcriptome data and clinical information of 526 HCC patients using multiple algorithms in R language and extensively described the copy number variation, prognostic and immune infiltration characteristics of cuproptosis related genes (CRGs). Then, the hub CRG related genes associated with prognosis through LASSO and Cox regression analyses and constructed a prognostic prediction model including multiple molecular markers and clinicopathological parameters through training cohorts, then this model was verified by test cohorts. On the basis of the model, the clinicopathological indicators, immune infiltration and tumor microenvironment characteristics of HCC patients were further explored via bioinformation analysis. Then, We further explored the key gene biological function by single-cell analysis, cell viability and transwell experiments. Meantime, we also explored the molecular docking of the hub genes.Results: We have screened 5 hub genes associated with HCC prognosis and constructed a prognosis prediction scoring model. And the model results showed that patients in the high-risk group had poor prognosis and the expression levels of multiple immune markers, including PD-L1, CD276 and CTLA4, were higher than those patients in the low-risk group. We found a significant correlation between risk score and M0 macrophages and memory CD4+ T cells. And the single-cell analysis and molecular experiments showed that BEX1 were higher expressed in HCC tissues and deletion inhibited the proliferation, invasion and migration and EMT pathway of HCC cells. Finally, it was observed that BEX1 could bind to sorafenib to form a stable conformation.Conclusion: The study not only revealed the multiomics characteristics of CRGs in HCC but also constructed a new high-accuracy prognostic prediction model. Meanwhile, BEX1 were also identified as hub genes that can mediate the cuproptosis of hepatocytes as potential therapeutic targets for HCC.

【 授权许可】

Unknown   
Copyright © 2023 Cao, Qi, Wu, Li and Yang.