Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Nov 15, 2023; 15(11): 1951-1973
Published online Nov 15, 2023. doi: 10.4251/wjgo.v15.i11.1951
Identification of necroptosis-related lncRNAs for prognosis prediction and screening of potential drugs in patients with colorectal cancer
Zhi-Hua Chen, Yi-Lin Lin, Shao-Qin Chen, Xiao-Yu Yang
Zhi-Hua Chen, Shao-Qin Chen, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China
Zhi-Hua Chen, Shao-Qin Chen, Department of Gastrointestinal Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian Province, China
Yi-Lin Lin, Peking University People’s Hospital, Beijing 100044, China.
Xiao-Yu Yang, School of Basic Medicine Sciences, Fujian Medical University, Fuzhou 350122, Fujian Province, China
Author contributions: Chen SQ and Yang XY designed this study; Chen ZH analyzed and wrote the manuscript; Lin YL and Chen ZH analyzed the data and completed the RT-PCR experiment; Chen ZH downloaded the data and performed statistical analysis; All the authors have read and approved the final manuscript.
Supported by the Joint Funds for the Innovation of Science and Technology, Fujian Province, No.2019Y9133.
Institutional review board statement: This data of this article was downloaded CRC RNA-Seq data, clinical follow-up information and copy number variation data from the SNP 6.0 chip in the TCGA database from the UCSC cancer browser , and the Gene Expression Omnibus (GEO) database. This study was approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University (NO. MRCTA, ECFAH of FMU[20190(21)]).
Institutional animal care and use committee statement: This artical had not use any animal, so there isnot need any “Institutional Animal Care and Use Committee Approval Form or Document”.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this work.
Data sharing statement: The datasets generated and analyzed during the current study are available in the TCGA repository [https://portal.gdc.cancer.gov/] and the GEO repository [www.ncbi.nlm.nih.gov/geo/]. We declare that the data and materials used to support the findings of this study are provided and included within the supplementary information files.
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: Xiao-Yu Yang, PhD, Full professor, School of Basic Medicine Sciences, Fujian Medical University, No. 1 Xuefu North Road, Minhou County, Fuzhou 350122, Fujian Province, China. yxyfj@163.com.
Received: May 16, 2023
Peer-review started: May 16, 2023
First decision: August 7, 2023
Revised: August 15, 2023
Accepted: September 14, 2023
Article in press: September 14, 2023
Published online: November 15, 2023
ARTICLE HIGHLIGHTS
Research background

Tumor recurrence and metastasis lead to a poor prognosis in colorectal cancer (CRC). Systemic treatments, including surgery, chemotherapeutics and targeted therapeutics, have reached a bottleneck for improving patient prognosis. Necroptosis induction significantly improves antitumor immunity by inducing the maturation of dendritic cells and activation of cytotoxic cluster of differentiation 8+ T cells, which play roles in antitumor immunity.

Research motivation

We aimed to explore the internal relationships and mechanisms of interaction between necroptosis-related long noncoding RNAs (lncRNAs) (NRLs) and the tumor microenvironment. As lncRNAs in bodily fluids are known to be new cancer biomarkers, we stratified CRC patients according to NRL expression levels, which allowed us to not only evaluate patient prognosis but also improve precision medicine in clinical practice. Additionally, we hoped to identify potential effective immunotherapeutic targets and drugs.

Research objectives

To identify a NRL signature and to comprehensively and multidimensionally evaluated the value of this signature, and its reliability for CRC prognosis prediction was assessed with clinical CRC data and compared with that of six other lncRNA signatures.

Research methods

Identification of NRLs and development and preliminary validation of the risk signature with univariate Cox analysis and multivariate Cox analysis. Then, the value of this signature was comprehensively and multidimensionally evaluated, and its reliability for CRC prognosis prediction was assessed with clinical CRC data and compared with that of six other lncRNA signatures. Gene Set Enrichment Analysis, tumor microenvironment (TME) analysis and half-maximal inhibitory concentration (IC50) prediction were also performed according to the risk score (RS) of the signature.

Research results

An 8-lncRNA signature significantly associated with overall survival (OS) was constructed, and its reliability was validated with clinical CRC data. Most of the areas under the receiver operating characteristic curves values for this signature were higher than those for the other six lncRNA signatures. OS, disease-specific survival and progression-free interval were all significantly poorer in the high-risk group. The RS of the signature showed good concordance with the predicted prognosis. Additionally, the calibration plots for this signature combined with clinical factors showed that this combination could effectively improve the ability to predict OS. The RS was correlated with tumor stage, lymph node metastasis and distant metastasis. Most of the enriched Kyoto Encyclopedia of Genes and Genomes and Gene Ontology terms were tumor metastasis-related pathways in the high-risk group; these patients showed greater infiltration of immunosuppressive cells, but less infiltration of infiltrating antitumor effector immune cells. We explored additional potential immune checkpoint genes and potential immunotherapeutic and chemotherapeutic drugs with relatively low IC50 values.

Research conclusions

We identified an NRL signature for CRC prognosis prediction and subtyping using lncRNA expression profiles. This signature will not only greatly improve the ability to predict CRC prognosis but also allow exploration of the reasons and mechanism underlying the increased TME infiltration of more immunosuppressive cells and decreased TME infiltration of antitumor effector immune cells in high-risk group patients, which leads to distant metastases. This signature found additional potential immune checkpoint genes and immunotherapeutic and chemotherapeutic drugs, and future in-depth research will identify more potential biomarkers and treatment targets for CRC.

Research perspectives

We identified an NRL signature with strong fidelity that could stably predict prognosis and might be an indicator of the TME of CRC. Furthermore, additional potential immunotherapeutic and chemotherapeutic drugs were explored.