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Exploration of a screening model for intrahepatic cholangiocarcinoma patients prone to cuproptosis and mechanisms of the susceptibility of CD274-knockdown intrahepatic cholangiocarcinoma cells to cuproptosis

Cancer Gene Therapy volume 30, pages 1663–1678 (2023)Cite this article

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Abstract

Intrahepatic cholangiocarcinoma (ICC) is a form of liver cancer with poor long-term survival rates that requires novel therapeutic methods. Our team’s previous research found that ICC patients prone to cuproptosis possessed a more satisfactory long-term prognosis and a more sensitive response to copper carrier Elesclomol. Thus, we aimed to identify new diagnostic and treatment strategies for ICC patients prone to cuproptosis and further explore the associated intracellular and extracellular mechanisms of ICC cells prone to cuproptosis. We employed FU-ICC (n = 255) as the training dataset, and validated our findings using SRRSH-ICC (from our center, n = 65), GSE26566 (n = 104), E-MTAB-6389 (n = 78), and scRNA-seq (n = 14) datasets. Single sample gene set enrichment analysis and subsequent unsupervised cluster analysis was conducted on the training dataset for the pan-programmed cell death gene set (including apoptosis, autophagy, ferroptosis, pyroptosis, necroptosis, and cuproptosis) to define and screen ICC patients prone to cuproptosis. We constructed a nomogram model using weighted gene co-expression network analysis and machine learning algorithms to predict ICC patients prone to cuproptosis, then explored its clinical value with multi-center transcriptome profiling. Furthermore, we validated the hub genes with in vitro and animal experiments to define ICC cells prone to cuproptosis. Ultimately, bulk and single-cell transcriptome profiling were utilized to explore the immune microenvironment of ICC cells prone to cuproptosis. Our nomogram model could help predict ICC patients prone to cuproptosis and possessed excellent prediction efficiency and clinical significance via internal and external verification. In vitro experiments demonstrated that ICC cells with siRNA-mediated knockdown of CD274 (PD-L1) and stimulation with elescomol-CuCl2 were prone to cuproptosis, and CD274-negative ICC cells could be defined as ICC cells prone to cuproptosis. The safety and feasibility of lenti-sh CD274+Elesclomol-CuCl2 as a therapeutic approach for ICC were verified using bioinformatics analysis and animal experiments. Bulk and single-cell transcriptome profiling indicated that the interactions between ICC cells prone to cuproptosis and monocytes/macrophages were particularly relevant. In conclusion, this study systematically and comprehensively explored cuproptosis in ICC for the first time. We constructed precise diagnostic and treatment strategies for ICC patients prone to cuproptosis and further explored the intracellular and extracellular mechanisms of ICC cells prone to cuproptosis. Further work with large prospective cohorts will help verify these conclusions.

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Fig. 1: Flow chart of the study design.
Fig. 2: Screening of ICC patients prone to cuproptosis.
Fig. 3: Screening of hub gene in ICC patients prone to cuproptosis.
Fig. 4: Construction and validation of nomogram model for predicting ICC patients prone to cuproptosis.
Fig. 5: The clinical application of the nomogram model——chemotherapy sensitivity analysis, immune infiltration analysis, and survival analysis.
Fig. 6: The hub genes were validated by in vitro experiments.
Fig. 7: Animal experiments demonstrated that the combination of shCD274 and Elesclomol-CuCl2 made ICC tumor prone to cuproptosis.
Fig. 8: The immune microenvironment of ICC patients prone to cuproptosis explored by single-cell transcriptome profiling.

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The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

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Acknowledgements

We thank J. Iacona, Ph.D., from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript. And we thank Figdraw (www.figdraw.com) for generating the Fig. 7A.

Funding

This study was supported by National Natural Science Foundation of China under Grant No. 82072625, Zhejiang Provincial Natural Science Foundation of China under Grant No. LQ22H160011.

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  1. These authors contributed equally: Zefeng Shen, Jingwei Cai, Liye Tao.

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  1. Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China

    Zefeng Shen, Jingwei Cai, Liye Tao, Junhao Zheng, Zhengtao Ye, Yang Liu, Haoyu Pan, Yali Wang, Junjie Xu & Xiao Liang

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XL, JJX, ZFS, JWC, and LYT are responsible for the conception, design, and writing of the article. ZFS, JWC, and JHZ are responsible for the data processing and analysis. ZFS, YLW, LYT, JWC, JHZ, YL, and HYP are responsible for collecting the original data. ZFS, XL, and JWC are responsible for reviewing and guiding the revision of the paper. All authors contributed to the article and approved the submitted version.

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Correspondence to Yali Wang, Junjie Xu or Xiao Liang.

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This study involving human participants was reviewed and approved by Ethics Committee in Clinical Research of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University (NO. 20201231-46). The data used in this article are all items that must be checked according to medical standards during the hospitalization, and collected retrospectively when designing the study, without adding any additional medical examination or test outside the normal diagnosis and treatment procedures.

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Shen, Z., Cai, J., Tao, L. et al. Exploration of a screening model for intrahepatic cholangiocarcinoma patients prone to cuproptosis and mechanisms of the susceptibility of CD274-knockdown intrahepatic cholangiocarcinoma cells to cuproptosis. Cancer Gene Ther 30, 1663–1678 (2023). https://doi.org/10.1038/s41417-023-00673-4

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