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Research Paper|Volume 15, Issue 24|pp 15084—15113

Copper metabolism-related risk score identifies hepatocellular carcinoma subtypes and SLC27A5 as a potential regulator of cuproptosis

Xiaoyan Li1,2, Jinping Wang3, Zongliang Guo4, Yong Ma5, Dawei Xu1, Daguang Fan6, Peng Dai6, Yifan Chen7, Qiongwen Liu8, Jinke Jiao8, Jinhan Fan8, Ningxue Wu8, Xin Li9, Guoyin Li8,10,11
  • 1Department of Blood Transfusion, Shanxi Provincial People’s Hospital, Affiliate of Shanxi Medical University, Taiyuan, Shanxi, China
  • 2Department of Central Laboratory, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, Shanxi, China
  • 3Department of Ultrasound, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, Shanxi, China
  • 4Department of General Surgery, Shanxi Province Cancer Hospital, Affiliated of Shanxi Medical University, Taiyuan, Shanxi, China
  • 5Department of Thoracic Surgery, Shanxi Province Cancer Hospital, Affiliated of Shanxi Medical University, Taiyuan, Shanxi, China
  • 6Department of Hepatobiliary and Pancreatic Surgery, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, Shanxi, China
  • 7College of Management, Zhejiang Shuren University, Hangzhou, Zhejiang, China
  • 8College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, Henan, China
  • 9Department of Geriatric Medicine, Shanxi Provincial People's Hospital, Affiliate of Shanxi Medical University, Taiyuan, Shanxi, China
  • 10MOE Key Laboratory of Modern Teaching Technology, Center for Teacher Professional Ability Development, Shaanxi Normal University, Xi’an, Shannxi, China
  • 11Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
* Equal contribution
Received: May 24, 2023Accepted: November 10, 2023Published: December 28, 2023
https://doi.org/10.18632/aging.205334

Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Aims: Dysregulated copper metabolism has been noticed in many types of cancer including hepatocellular carcinoma (HCC); however, a comprehensive understanding about this dysregulation still remains unclear in HCC.

Methods: A set of bioinformatic tools was integrated to analyze the expression and prognostic significance of copper metabolism-related genes. A related risk score, termed as CMscore, was developed via univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression. Pathway enrichment analyses and tumor immune cell infiltration were further investigated in CMscore stratified HCC patients. Weighted correlation network analysis (WGCNA) was used to identify potential regulator of cuproptosis.

Results: Copper metabolism was dysregulated in HCC. HCC patients in the high-CMscore group showed a significantly lower overall survival (OS) and enriched in most cancer-related pathways. Besides, HCC patients with high CMscore had higher expression of pro-tumor immune infiltrates and immune checkpoints. Moreover, cancer patients with high CMscore from two large cohorts exhibited significantly prolonged survival time after immunotherapy. WGCNA and subsequently correlation analysis revealed that SLC27A5 might be a potential regulator of cuproptosis in HCC. In vitro experiments revealed that SLC27A5 inhibited cell proliferation and migration of HCC cells and could upregulate FDX1, the key regulator of cuproptosis.

Significance: The CMscore is helpful in clustering HCC patients with distinct prognosis, gene mutation signatures, and sensitivity to immunotherapy. SLC27A5 might serve as a potential target in the induction of cuproptosis in HCC.