EREG is the core onco-immunological biomarker of cuproptosis and mediates the cross-talk between VEGF and CD99 signaling in glioblastoma.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Epiregulin* ; Glioblastoma*/genetics ; Glioma*/genetics ; Apoptosis*; Humans ; 12E7 Antigen ; Biomarkers ; Intercellular Signaling Peptides and Proteins ; Vascular Endothelial Growth Factor A

Background: Glioma is the most prevalent primary tumor of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant form of glioma with an extremely poor prognosis. A novel, regulated cell death form of copper-induced cell death called "cuproptosis" provides a new prospect for cancer treatment by regulating cuproptosis.
Methods: Data from bulk RNA sequencing (RNA-seq) analysis (The Cancer Genome Atlas cohort and Chinese Glioma Genome Atlas cohort) and single cell RNA-seq (scRNA-seq) analysis were integrated to reveal their relationships. A scoring system was constructed according to the cuproptosis-related gene expression, and core genes were experimentally verified using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Moreover, cell counting kit-8 (CCK8), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, transwell, and flow cytometry cell cycle were performed to evaluate cell proliferation, invasion, and migration.
Results: The Cuproptosis Activation Scoring (CuAS) Model has stable and independent prognostic efficacy, as verified by two CGGA datasets. Epiregulin (EREG), the gene of the model has the most contributions in the principal component analysis (PCA), is an onco-immunological gene that can affect immunity by influencing the expression of programmed death-ligand 1 (PD-L1) and mediate the process of cuproptosis by influencing the expression of ferredoxin 1 (FDX1). Single cell transcriptome analysis revealed that high CuAS GBM cells are found in vascular endothelial growth factor A (VEGFA) + malignant cells. Oligodendrocyte transcription factor 1 (OLIG1) + malignant is the original clone, and VEGF and CD99 are the differential pathways of specific cell communication between the high and low CuAS groups. This was also demonstrated by immunofluorescence in the tissue sections. Furthermore, CuAS has therapeutic potential for immunotherapy, and we predict that many drugs (methotrexate, NU7441, KU -0063794, GDC-0941, cabozantinib, and NVP-BEZ235) may be used in patients with high CuAS.
Conclusion: EREG is the core onco-immunological biomarker of CuAS and modulates the cross-talk between VEGF and CD99 signaling in glioblastoma, and CuAS may provide support for immunotherapy and chemotherapy.
(© 2023. The Author(s).)

Cell. 2019 Mar 7;176(6):1248-1264. (PMID: 30849371)
Purinergic Signal. 2016 Jun;12(2):303-12. (PMID: 26910734)
Cancer Cell. 2010 May 18;17(5):510-22. (PMID: 20399149)
Front Mol Biosci. 2022 Mar 04;9:841814. (PMID: 35309510)
Oxid Med Cell Longev. 2021 Nov 09;2021:9107857. (PMID: 34804371)
Neurooncol Adv. 2020 Aug 08;2(1):vdaa091. (PMID: 33409495)
Genomics Proteomics Bioinformatics. 2020 Apr;18(2):120-128. (PMID: 32858223)
Mol Carcinog. 2019 Sep;58(9):1581-1588. (PMID: 31062416)
Cell Res. 2022 May;32(5):417-418. (PMID: 35354936)
J Transl Med. 2022 Jul 25;20(1):335. (PMID: 35879775)
BMC Bioinformatics. 2013 Jan 16;14:7. (PMID: 23323831)
J Cell Mol Med. 2019 Jun;23(6):4375-4385. (PMID: 31001929)
Immunity. 2019 Aug 20;51(2):411-412. (PMID: 31433971)
Genome Biol. 2017 Nov 15;18(1):220. (PMID: 29141660)
Pharmacol Rev. 2018 Jul;70(3):412-445. (PMID: 29669750)
Brain Sci. 2020 Jan 31;10(2):. (PMID: 32024010)
Neuroscience. 2017 Mar 27;346:298-308. (PMID: 28147244)
Brief Bioinform. 2021 May 20;22(3):. (PMID: 32510568)
Adv Mater. 2019 Dec;31(51):e1904197. (PMID: 31595562)
J Cell Commun Signal. 2018 Mar;12(1):55-68. (PMID: 29305692)
Nat Chem Biol. 2019 Jul;15(7):681-689. (PMID: 31133756)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Acta Neuropathol. 2015 Jun;129(6):829-48. (PMID: 25943888)
Sci Transl Med. 2021 Jun 30;13(600):. (PMID: 34193614)
CNS Neurosci Ther. 2020 Sep;26(9):981-989. (PMID: 32488994)
Methods Mol Biol. 2012;821:349-59. (PMID: 22125077)
Biochim Biophys Acta Mol Cell Res. 2021 Jan;1868(1):118867. (PMID: 32979421)
Methods Mol Biol. 2018;1711:243-259. (PMID: 29344893)
Cell Mol Immunol. 2022 Aug;19(8):867-868. (PMID: 35459854)
Cancer Cell. 2021 Jun 14;39(6):779-792.e11. (PMID: 34087162)
Oncology. 2005;69 Suppl 3:4-10. (PMID: 16301830)
Science. 2022 Mar 18;375(6586):1254-1261. (PMID: 35298263)
Mol Neurobiol. 2020 May;57(5):2461-2478. (PMID: 32152825)
Neuro Oncol. 2014 Jul;16(7):960-70. (PMID: 24470554)
Neuro Oncol. 2018 Jan 22;20(2):259-267. (PMID: 29036345)
Nat Commun. 2013;4:2612. (PMID: 24113773)
Cell Death Differ. 2018 Mar;25(3):486-541. (PMID: 29362479)
Cell Rep. 2018 Nov 6;25(6):1436-1445.e3. (PMID: 30404000)
Cancer Lett. 2015 Oct 10;367(1):58-68. (PMID: 26188279)

Keywords: Bulk RNA-seq analysis; CD99; Cuproptosis; Flow cytometry cell cycle; Immune microenvironment; Immunohistochemistry; Single cell RNA-seq; Transwell assays; VEGFA

0 (12E7 Antigen)
0 (Biomarkers)
0 (CD99 protein, human)
0 (Epiregulin)
0 (EREG protein, human)
0 (Intercellular Signaling Peptides and Proteins)
0 (Vascular Endothelial Growth Factor A)

Date Created: 20230116 Date Completed: 20230119 Latest Revision: 20230201

20250114

PMC9843967

10.1186/s12967-023-03883-4

36647156