Copyright
©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Cuproptosis-related long non-coding RNAs model that effectively predicts prognosis in hepatocellular carcinoma
En-Min Huang, Ning Ma, Tao Ma, Jun-Yi Zhou, Wei-Sheng Yang, Chuang-Xiong Liu, Ze-Hui Hou, Shuang Chen, Zhen Zong, Bing Zeng, Ying-Ru Li, Tai-Cheng Zhou
En-Min Huang, Ning Ma, Tao Ma, Wei-Sheng Yang, Chuang-Xiong Liu, Ze-Hui Hou, Shuang Chen, Bing Zeng, Ying-Ru Li, Tai-Cheng Zhou, Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
En-Min Huang, Ning Ma, Tao Ma, Jun-Yi Zhou, Wei-Sheng Yang, Chuang-Xiong Liu, Ze-Hui Hou, Shuang Chen, Bing Zeng, Ying-Ru Li, Tai-Cheng Zhou, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
Jun-Yi Zhou, Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
Zhen Zong, Department of Gastroenterological Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang 330006, Jiangxi Province, China
Author contributions: Zhou TC, Li YR, Zeng B, Zong Z, and Chen S conceived the study and its design, and provided administrative support; Huang EM, Ma N, and Ma T were involved in data analyses and wrote, reviewed, and edited the manuscript; Zhou JY, Yang WS, Liu CX, and Hou ZH contributed data analysis and reviewed the manuscript; all authors read and approved the final manuscript, and contributed to the article and approved the submitted version for publication.
Supported by the National Key Clinical Discipline, the Basic and Applied Basic Research Fund Project of Guangdong Province, No. 2021A1515410004 and No. 2019A1515011200; National Natural Science Foundation of China, No. 81973858 and No. 82172790; and Science and Technology Plan Project of Qingyuan City, No. 2019A028.
Institutional review board statement: The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Since the present study is a bioinformatics work that did not involve animal or human specimens, there is no requirement for ethical permission from our institution or an ethics number.
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement: Publicly available datasets were analyzed in this study. These data can be found here:
https://portal.gdc.cancer.gov/repository. Technical appendix, statistical code, and dataset available from the corresponding author at
zhoutch3@mail.sysu.edu.cn.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Tai-Cheng Zhou, MD, PhD, Associate Professor, Doctor, Surgeon, Surgical Oncologist, Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital, Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Guangzhou 510655, Guangdong Province, China. zhoutch3@mail.sysu.edu.cn
Received: June 24, 2022
Peer-review started: June 24, 2022
First decision: July 18, 2022
Revised: July 29, 2022
Accepted: August 17, 2022
Article in press: August 17, 2022
Published online: October 15, 2022
ARTICLE HIGHLIGHTS
Research background
Cuproptosis, a form of programmed cell death recently found to result from the binding of accumulated intracellular copper to aliphatic components of the tricarboxylic acid cycle, causes aggregation of lipoacylated proteins and loss of iron-sulfur cluster proteins. However, factors crucial to the regulation of cuproptosis remain unelucidated.
Research motivation
We hypothesized that abnormal expression of genes relevant to the copper metabolism pathway could serve as prognostic and therapeutic markers in hepatocellular carcinoma (HCC).
Research objectives
To identify long-chain non-coding RNAs (lncRNAs) associated with cuproptosis in order to predict the prognosis of patients with HCC.
Research methods
Using RNA sequencing data from The Cancer Genome Atlas Live Hepatocellular Carcinoma (TCGA-LIHC), a co-expression network of cuproptosis-related genes and lncRNAs was constructed. For HCC prognosis, we developed a cuproptosis-related lncRNA signature (CupRLSig) using univariate Cox, Lasso, and multivariate Cox regression analyses. Kaplan-Meier analysis was used to compare overall survival among high- and low-risk groups stratified by median CupRLSig risk score. Furthermore, comparisons of functional annotation, immune infiltration, somatic mutation, tumor mutation burden (TMB), and pharmacologic options were made between high- and low-risk groups.
Research results
The high-risk group identified by CupRLSig was associated with poorer overall survival and progression-free survival. Less activation of natural killer cells and more infiltration of regulatory T cells in the high-risk group may explain the worse outcomes. Based on checkpoint gene expression (CD276, CTLA-4, and PDCD-1) and tumor immune dysfunction and rejection (TIDE) scores, high-risk patients may respond better to immunotherapy.
Research conclusions
The lncRNA signature, CupRLSig, constructed in this study is valuable in prognostic estimation in the setting of HCC. Importantly, CupRLSig probably also predicts levels of immune infiltration and the potential efficacy of tumor immunotherapy, chemotherapy, and targeted therapy.
Research perspectives
We believe that we can expand the bulk-sequencing-generated lncRNA model to the standard care of HCC patients if sufficient external data is available to validate the predictive efficacy of CupRLSig.
