Copper and cuproptosis-related genes in hepatocellular carcinoma: therapeutic biomarkers targeting tumor immune microenvironment and immune checkpoints

Xiaoqiang Wang; Dongfang Chen; Yumiao Shi; Jiamei Luo; Yiqi Zhang; Xiaohong Yuan; Chaojin Zhang; Huigang Shu; Weifeng Yu; Jie Tian

doi:10.3389/fimmu.2023.1123231

Copper and cuproptosis-related genes in hepatocellular carcinoma: therapeutic biomarkers targeting tumor immune microenvironment and immune checkpoints

Front Immunol. 2023 Apr 20:14:1123231. doi: 10.3389/fimmu.2023.1123231. eCollection 2023.

Authors

Affiliations

¹ Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
² Department of Anesthesiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
³ Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.

Abstract

Background: Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, exhibits high immune heterogeneity and mortality. Emerging studies suggest that copper (Cu) plays a key role in cell survival. However, the relationship between Cu and tumor development remains unclear.

Methods: We investigated the effects of Cu and cuproptosis-related genes (CRGs) in patients with HCC in the TCGA-LIHC (The Cancer Genome Atlas-Liver cancer, n = 347) and ICGC-LIRI-JP (International Cancer Genome Consortium-Liver Cancer-Riken-Japan, n = 203) datasets. Prognostic genes were identified by survival analysis, and a least absolute shrinkage and selection operator (Lasso) regression model was constructed using the prognostic genes in the two datasets. Additionally, we analyzed differentially expressed genes and signal pathway enrichment. We also evaluated the effects of CRGs on tumor immune cell infiltration and their co-expression with immune checkpoint genes (ICGs) and performed validation in different tumor immune microenvironments (TIMs). Finally, we performed validation using clinical samples and predicted the prognosis of patients with HCC using a nomogram.

Results: A total of 59 CRGs were included for analysis, and 15 genes that significantly influenced the survival of patients in the two datasets were identified. Patients were grouped by risk scores, and pathway enrichment analysis suggested that immune-related pathways were substantially enriched in both datasets. Tumor immune cell infiltration analysis and clinical validation revealed that PRNP (Prion protein), SNCA (Synuclein alpha), and COX17 (Cytochrome c oxidase copper chaperone COX17) may be closely correlated with immune cell infiltration and ICG expression. A nomogram was constructed to predict the prognosis of patients with HCC using patients' characteristics and risk scores.

Conclusion: CRGs may regulate the development of HCC by targeting the TIM and ICGs. CRGs such as PRNP, SNCA, and COX17 could be promising targets for HCC immune therapy in the future.

Keywords: copper; cuproptosis; hepatocellular carcinoma; immune checkpoints; tumor immune microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis*
Biomarkers
Carcinoma, Hepatocellular* / genetics
Copper
Genes, Regulator
Humans
Liver Neoplasms* / genetics
Tumor Microenvironment / genetics

Substances

Biomarkers
Copper

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 82171177 to JT and No. 32030043 and 81971223 to WY); the Clinical Research Plan of SHDC (No. SHDC2020CR4062 to JT); The Shanghai Pudong New Area Municipal Commission of Health and Family Planning Funding(PWZxq2017-06 to WY); the Shanghai Municipal Key Clinical Specialty (shslczdzk03601 to WY); the Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation (No. 20DZ2254200); the Shanghai Municipal Education Commission (No. 2019-01-07-00-01-E00074); the Minhang District Natural Science Research Project (No. 2022MHZ037 to DC); and the Zhejiang Medical Health Science and Technology Project (No. 2021RC047 to XY).