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A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma

BACKGROUND: Neuroblastoma (NB) is the most frequent solid tumor in pediatrics, which accounts for roughly 15% of cancer-related mortality in children. NB exhibited genetic, morphologic, and clinical heterogeneity, which limited the efficacy of available therapeutic approaches. Recently, a new term ‘...

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Autores principales: Tian, Xiao-Mao, Xiang, Bin, Yu, Yi-Hang, Li, Qi, Zhang, Zhao-Xia, Zhanghuang, Chenghao, Jin, Li-Ming, Wang, Jin-Kui, Mi, Tao, Chen, Mei-Lin, Liu, Feng, Wei, Guang-Hui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9540510/
https://www.ncbi.nlm.nih.gov/pubmed/36211401
http://dx.doi.org/10.3389/fimmu.2022.999849
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author Tian, Xiao-Mao
Xiang, Bin
Yu, Yi-Hang
Li, Qi
Zhang, Zhao-Xia
Zhanghuang, Chenghao
Jin, Li-Ming
Wang, Jin-Kui
Mi, Tao
Chen, Mei-Lin
Liu, Feng
Wei, Guang-Hui
author_facet Tian, Xiao-Mao
Xiang, Bin
Yu, Yi-Hang
Li, Qi
Zhang, Zhao-Xia
Zhanghuang, Chenghao
Jin, Li-Ming
Wang, Jin-Kui
Mi, Tao
Chen, Mei-Lin
Liu, Feng
Wei, Guang-Hui
author_sort Tian, Xiao-Mao
collection PubMed
description BACKGROUND: Neuroblastoma (NB) is the most frequent solid tumor in pediatrics, which accounts for roughly 15% of cancer-related mortality in children. NB exhibited genetic, morphologic, and clinical heterogeneity, which limited the efficacy of available therapeutic approaches. Recently, a new term ‘cuproptosis’ has been used to denote a unique biological process triggered by the action of copper. In this instance, selectively inducing copper death is likely to successfully overcome the limitations of conventional anticancer drugs. However, there is still a gap regarding the role of cuproptosis in cancer, especially in pediatric neuroblastoma. METHODS: We characterized the specific expression of cuproptosis-related genes (CRGs) in NB samples based on publicly available mRNA expression profile data. Consensus clustering and Lasso-Cox regression analysis were applied for CRGs in three independent cohorts. ESTIMATE and Xcell algorithm was utilized to visualize TME score and immune cell subpopulations’ relative abundances. Tumor Immune Dysfunction and Exclusion (TIDE) score was used to predict tumor response to immune checkpoint inhibitors. To decipher the underlying mechanism, GSVA was applied to explore enriched pathways associated with cuproptosis signature and Connectivity map (CMap) analysis for drug exploration. Finally, qPCR verified the expression levels of risk-genes in NB cell lines. In addition, PDHA1 was screened and further validated by immunofluorescence in human clinical samples and loss-of-function assays. RESULTS: We initially classified NB patients according to CRGs and identified two cuproptosis-related subtypes that were associated with prognosis and immunophenotype. After this, a cuproptosis-related prognostic model was constructed and validated by LASSO regression in three independent cohorts. This model can accurately predict prognosis, immune infiltration, and immunotherapy responses. These genes also showed differential expression in various characteristic groups of all three datasets and NB cell lines. Loss-of-function experiments indicated that PDHA1 silencing significantly suppressed the proliferation, migration, and invasion, in turn, promoted cell cycle arrest at the S phase and apoptosis of NB cells. CONCLUSIONS: Taken together, this study may shed light on new research areas for NB patients from the cuproptosis perspective.
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spelling pubmed-95405102022-10-08 A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma Tian, Xiao-Mao Xiang, Bin Yu, Yi-Hang Li, Qi Zhang, Zhao-Xia Zhanghuang, Chenghao Jin, Li-Ming Wang, Jin-Kui Mi, Tao Chen, Mei-Lin Liu, Feng Wei, Guang-Hui Front Immunol Immunology BACKGROUND: Neuroblastoma (NB) is the most frequent solid tumor in pediatrics, which accounts for roughly 15% of cancer-related mortality in children. NB exhibited genetic, morphologic, and clinical heterogeneity, which limited the efficacy of available therapeutic approaches. Recently, a new term ‘cuproptosis’ has been used to denote a unique biological process triggered by the action of copper. In this instance, selectively inducing copper death is likely to successfully overcome the limitations of conventional anticancer drugs. However, there is still a gap regarding the role of cuproptosis in cancer, especially in pediatric neuroblastoma. METHODS: We characterized the specific expression of cuproptosis-related genes (CRGs) in NB samples based on publicly available mRNA expression profile data. Consensus clustering and Lasso-Cox regression analysis were applied for CRGs in three independent cohorts. ESTIMATE and Xcell algorithm was utilized to visualize TME score and immune cell subpopulations’ relative abundances. Tumor Immune Dysfunction and Exclusion (TIDE) score was used to predict tumor response to immune checkpoint inhibitors. To decipher the underlying mechanism, GSVA was applied to explore enriched pathways associated with cuproptosis signature and Connectivity map (CMap) analysis for drug exploration. Finally, qPCR verified the expression levels of risk-genes in NB cell lines. In addition, PDHA1 was screened and further validated by immunofluorescence in human clinical samples and loss-of-function assays. RESULTS: We initially classified NB patients according to CRGs and identified two cuproptosis-related subtypes that were associated with prognosis and immunophenotype. After this, a cuproptosis-related prognostic model was constructed and validated by LASSO regression in three independent cohorts. This model can accurately predict prognosis, immune infiltration, and immunotherapy responses. These genes also showed differential expression in various characteristic groups of all three datasets and NB cell lines. Loss-of-function experiments indicated that PDHA1 silencing significantly suppressed the proliferation, migration, and invasion, in turn, promoted cell cycle arrest at the S phase and apoptosis of NB cells. CONCLUSIONS: Taken together, this study may shed light on new research areas for NB patients from the cuproptosis perspective. Frontiers Media S.A. 2022-09-23 /pmc/articles/PMC9540510/ /pubmed/36211401 http://dx.doi.org/10.3389/fimmu.2022.999849 Text en Copyright © 2022 Tian, Xiang, Yu, Li, Zhang, Zhanghuang, Jin, Wang, Mi, Chen, Liu and Wei https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Tian, Xiao-Mao
Xiang, Bin
Yu, Yi-Hang
Li, Qi
Zhang, Zhao-Xia
Zhanghuang, Chenghao
Jin, Li-Ming
Wang, Jin-Kui
Mi, Tao
Chen, Mei-Lin
Liu, Feng
Wei, Guang-Hui
A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma
title A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma
title_full A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma
title_fullStr A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma
title_full_unstemmed A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma
title_short A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma
title_sort novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9540510/
https://www.ncbi.nlm.nih.gov/pubmed/36211401
http://dx.doi.org/10.3389/fimmu.2022.999849
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