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

作者全名："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"

作者地址："[Tian, Xiao-Mao; Xiang, Bin; Yu, Yi-Hang; Li, Qi; Zhang, Zhao-Xia; Jin, Li-Ming; Wang, Jin-Kui; Mi, Tao; Chen, Mei-Lin; Liu, Feng; Wei, Guang-Hui] Chongqing Med Univ, Dept Urol, Childrens Hosp, Chongqing, Peoples R China; [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] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorders, Chongqing Key Lab Pediat,Childrens Hosp,China Int, Chongqing, Peoples R China; [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] Chongqing Key Lab Children Urogenital Dev & Tissue, Chongqing, Peoples R China"

通信作者："Liu, F; Wei, GH (通讯作者)，Chongqing Med Univ, Dept Urol, Childrens Hosp, Chongqing, Peoples R China.; Liu, F; Wei, GH (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorders, Chongqing Key Lab Pediat,Childrens Hosp,China Int, Chongqing, Peoples R China.; Liu, F; Wei, GH (通讯作者)，Chongqing Key Lab Children Urogenital Dev & Tissue, Chongqing, Peoples R China."

来源：FRONTIERS IN IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000869797900001

JCR分区：Q1

影响因子：7.3

年份：2022

卷号：13

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：neuroblastoma; cuproptosis; tumor immune microenvironment; prognosis; immunotherapy

摘要："BackgroundNeuroblastoma (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. MethodsWe 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. ResultsWe 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. ConclusionsTaken together, this study may shed light on new research areas for NB patients from the cuproptosis perspective."

基金机构：Natural Science Foundation of Chongqing [cstc2021jcyj-msxmX0345]; Medical Scientific Research Project of Chongqing [2022GDRC009]; general project of clinical medicine research of Children's Hospital of Chongqing Medical University [NCRC-2019-GP-08]

基金资助正文："This work was supported by the Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0345), the Medical Scientific Research Project of Chongqing (NO.2022GDRC009), the general project of clinical medicine research of Children's Hospital of Chongqing Medical University (NCRC-2019-GP-08)."