Identification of cuproptosis-related subtypes and the development of a prognostic model in glioma

Zhaoping Wu; Wei Li; Hecheng Zhu; Xuewen Li; Yi Zhou; Quan Chen; Haoxuan Huang; Wenlong Zhang; Xingjun Jiang; Caiping Ren

doi:10.3389/fgene.2023.1124439

Identification of cuproptosis-related subtypes and the development of a prognostic model in glioma

Front Genet. 2023 Mar 1:14:1124439. doi: 10.3389/fgene.2023.1124439. eCollection 2023.

Authors

Zhaoping Wu¹, Wei Li^{2

3}, Hecheng Zhu⁴, Xuewen Li⁴, Yi Zhou¹, Quan Chen¹, Haoxuan Huang¹, Wenlong Zhang¹, Xingjun Jiang¹, Caiping Ren^{1

5

6}

Affiliations

¹ Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
³ Institute of Clinical Pharmacology, Central South University, Changsha, China.
⁴ Changsha Kexin Cancer Hospital, Changsha, Hunan, China.
⁵ Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China.
⁶ The NHC Key Laboratory of Carcinogenesis and The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China.

Abstract

Introduction: A copper-dependent cell death, cuproptosis, involves copper binding with lipoylated tricarboxylic acid (TCA) cycle components. In cuproptosis, ferredoxin 1 (FDX1) and lipoylation act as key regulators. The mechanism of cuproptosis differs from the current knowledge of cell death, which may invigorate investigations into copper's potential as a cancer treatment. An extremely dismal prognosis is associated with gliomas, the most prevalent primary intracranial tumor. In patients with glioma, conventional therapies, such as surgery and chemotherapy, have shown limited improvement. A variety of cell death modes have been confirmed to be operative in glioma oncogenesis and participate in the tumor microenvironment (TME), implicated in glioma development and progression. In this study, we aimed to explore whether cuproptosis influences glioma oncogenesis. Methods: Gene expression profiles related to cuproptosis were comprehensively evaluated by comparing adjacent tissues from glioma tissues in The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/) database. Gene expression, prognostic, clinical, and pathological data of lower-grade gliomas (LGG) and glioblastoma were retrieved from TCGA and Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases. The datasets were managed by "Combat" algorithm to eliminate batch effects and then combined. A consensus clustering algorithm based on the Partitioning Around Medoid (PAM) algorithm was used to classified 725 patients with LGG and glioblastoma multiforme (GBM) into two cuproptosis subtypes. According to the differentially expressed genes in the two cuproptosis subtypes, 725 patients were divided into 2 gene subtypes. Additionally, a scoring system that associated with TME was constructed to predict patient survival and patient immunotherapy outcomes. Furthermore, we constructed a prognostic CRG-score and nomogram system to predict the prognosis of glioma patients. 95 tissue specimens from 83 glioma patients undergoing surgical treatment were collected, including adjacent tissues. Using immunohistochemistry and RT-qPCR, we verified cuproptosis-related genes expression and CRG-score predictive ability in these clinical samples. Results: Our results revealed extensive regulatory mechanisms of cuproptosis-related genes in the cell cycle, TME, clinicopathological characteristics, and prognosis of glioma. We also developed a prognostic model based on cuproptosis. Through the verifications of database and clinical samples, we believe that cuproptosis affects the prognosis of glioma and potentially provides novel glioma research approaches. Conclusion: We suggest that cuproptosis has potential importance in treating gliomas and could be utilized in new glioma research efforts.

Keywords: cuproptosis; gene subtypes; glioma; prognostic model; tumor microenvironment.

Grants and funding

This study was supported by the National Natural Science Foundation of China (82071399, 81773179, 30871246, 81070993 and 81472355), Provincial Natural Science Foundation of Hunan (2020JJ4771, 2016JJ2172), National Key Research and Development Program of China (2016YFC1101502), Hunan Provincial Science and Technology Department (2014FJ6006), Independent Exploration and Innovation Project of Central South University (2020zzts773).