Comprehensive Analysis Identifies Ubiquitin Ligase FBXO42 As a Tumor-promoting Factor in Neuroblastoma

Overview

Journal Sci Rep

Specialty Science

Date 2024 Aug 12

PMID 39134694

Authors

Jianwu Zhou

Qijun Li

Xiaobin Deng

Liang Peng

Jian Sun

Yao Zhang

Yifei Du

Affiliations

Soon will be listed here.

Abstract

Neuroblastoma, the deadliest solid tumor in children, exhibits alarming mortality rates, particularly among high-risk cases. To enhance survival rates, a more precise risk stratification for patients is imperative. Utilizing proteomic data from 34 cases with or without N-Myc amplification, we identified 28 differentially expressed ubiquitination-related proteins (URGs). From these, a prognostic signature comprising 6 URGs was constructed. A nomogram incorporating clinical-pathological parameters yielded impressive AUC values of 0.88, 0.93, and 0.95 at 1, 3, and 5 years, respectively. Functional experiments targeting the E3 ubiquitin ligase FBXO42, a component of the prognostic signature, revealed its TP53-dependent promotion of neuroblastoma cell proliferation. In conclusion, our ubiquitination-related prognostic model robustly predicts patient outcomes, guiding clinical decisions. Additionally, the newfound pro-proliferative role of FBXO42 offers a novel foundation for understanding the molecular mechanisms of neuroblastoma.

References

Racle J, de Jonge K, Baumgaertner P, Speiser D, Gfeller D . Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data. Elife. 2017; 6. PMC: 5718706. DOI: 10.7554/eLife.26476. View

Hu J, Song F, Kang W, Xia F, Song Z, Wang Y . Integrative analysis of multi-omics data for discovery of ferroptosis-related gene signature predicting immune activity in neuroblastoma. Front Pharmacol. 2023; 14:1162563. PMC: 10373597. DOI: 10.3389/fphar.2023.1162563. View

Komander D, Clague M, Urbe S . Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009; 10(8):550-63. DOI: 10.1038/nrm2731. View

Hartlieb S, Sieverling L, Nadler-Holly M, Ziehm M, Toprak U, Herrmann C . Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome. Nat Commun. 2021; 12(1):1269. PMC: 7904810. DOI: 10.1038/s41467-021-21247-8. View

Liang R, Cheng A, Lu S, Zhang X, Ren M, Lin J . Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy. Int J Biol Sci. 2024; 20(7):2779-2789. PMC: 11077380. DOI: 10.7150/ijbs.95484. View

Kanehisa M . Toward understanding the origin and evolution of cellular organisms. Protein Sci. 2019; 28(11):1947-1951. PMC: 6798127. DOI: 10.1002/pro.3715. View

Zhang W, Chen J, Keyhani N, Zhang Z, Li S, Xia Y . Comparative transcriptomic analysis of immune responses of the migratory locust, Locusta migratoria, to challenge by the fungal insect pathogen, Metarhizium acridum. BMC Genomics. 2015; 16:867. PMC: 4624584. DOI: 10.1186/s12864-015-2089-9. View

Teng M, Love M, Davis C, Djebali S, Dobin A, Graveley B . A benchmark for RNA-seq quantification pipelines. Genome Biol. 2016; 17:74. PMC: 4842274. DOI: 10.1186/s13059-016-0940-1. View

Robert C, Watson M . Errors in RNA-Seq quantification affect genes of relevance to human disease. Genome Biol. 2015; 16:177. PMC: 4558956. DOI: 10.1186/s13059-015-0734-x. View

10.

Chen W, Lin P, Bai J, Fang Y, Zhang B . Establishment and validation of a nomogram to predict cancer-specific survival in pediatric neuroblastoma patients. Front Pediatr. 2023; 11:1105922. PMC: 10020339. DOI: 10.3389/fped.2023.1105922. View

11.

Veas-Perez de Tudela M, Delgado-Esteban M, Cuende J, Bolanos J, Almeida A . Human neuroblastoma cells with MYCN amplification are selectively resistant to oxidative stress by transcriptionally up-regulating glutamate cysteine ligase. J Neurochem. 2010; 113(4):819-25. DOI: 10.1111/j.1471-4159.2010.06648.x. View

12.

Dewson G, Eichhorn P, Komander D . Deubiquitinases in cancer. Nat Rev Cancer. 2023; 23(12):842-862. DOI: 10.1038/s41568-023-00633-y. View

13.

Yin T, Wen J, Xu S, Chen L, Zhang Z, Pan S . An E3 ubiquitin-proteasome gene signature for predicting prognosis in patients with pancreatic cancer. Front Immunol. 2024; 14:1332626. PMC: 10830689. DOI: 10.3389/fimmu.2023.1332626. View

14.

Schleiermacher G, Janoueix-Lerosey I, Delattre O . Recent insights into the biology of neuroblastoma. Int J Cancer. 2014; 135(10):2249-61. DOI: 10.1002/ijc.29077. View

15.

Meng X, Li H, Fang E, Feng J, Zhao X . Comparison of Stage 4 and Stage 4s Neuroblastoma Identifies Autophagy-Related Gene and LncRNA Signatures Associated With Prognosis. Front Oncol. 2020; 10:1411. PMC: 7466450. DOI: 10.3389/fonc.2020.01411. View

16.

Zhang J, Liu L, Wang Z, Hou M, Dong Z, Yu J . Ubiquitin-proteasome system-based signature to predict the prognosis and drug sensitivity of hepatocellular carcinoma. Front Pharmacol. 2023; 14:1172908. PMC: 10166894. DOI: 10.3389/fphar.2023.1172908. View

17.

Tian X, Xiang B, Yu Y, Li Q, Zhang Z, Zhanghuang C . A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma. Front Immunol. 2022; 13:999849. PMC: 9540510. DOI: 10.3389/fimmu.2022.999849. View

18.

Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M . KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2022; 51(D1):D587-D592. PMC: 9825424. DOI: 10.1093/nar/gkac963. View

19.

Luo X, Wang Y, Zhang H, Chen G, Sheng J, Tian X . Identification of a Prognostic Signature for Ovarian Cancer Based on Ubiquitin-Related Genes Suggesting a Potential Role for FBXO9. Biomolecules. 2023; 13(12). PMC: 10742228. DOI: 10.3390/biom13121724. View

20.

Chen Y, Li Z, Zhou G, Sun Y . An Immune-Related Gene Prognostic Index for Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2020; 27(1):330-341. DOI: 10.1158/1078-0432.CCR-20-2166. View