今日学术问题发现 | 兄弟借一步说话，看你是不是火眼金睛
Affiliations :
1.Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, SE-75185 Uppsala, Sweden
2.In-Vivo Electrophysiology Unit, Behavioral Neuroscience Branch, National Institute on Drug Abuse (NIDA)-Intramural Research Program (IRP), National Institute of Health, Baltimore, MD, USA
3.Indian Institute of Technology, School of Biomedical Engineering, Department of Biomaterials, Banaras Hindu University, Varanasi 221005, India
4.Department Neurosciences, University of Basque Country, Bilbao, Spain
5.Department of Clinical Neurosciences, University Hospital, University of Medicine and Pharmacy, Cluj-Napoca, Romania
6.Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
7.International Experimental CNS Injury and Repair (IECNSIR), Uppsala University Hospital
Abstract:
Background Radiotherapy is the frst-line regimen for treating oral squamous cell carcinoma (OSCC) in current clin‑ics. However, the development of therapeutic resistance impacts the anticancer efcacy of irradiation in a subpopu‑lation of OSCC patients. As a result, discovering a valuable biomarker to predict radiotherapeutic efectiveness and uncovering the molecular mechanism for radioresistance are clinical issues in OSCC.
Methods:
Three OSCC cohorts from The Cancer Genome Atlas (TCGA), GSE42743 dataset and Taipei Medical Univer‑sity Biobank were enrolled to examine the transcriptional levels and prognostic signifcance of neuronal precursor
cell-expressed developmentally downregulated protein 8 (NEDD8). Gene set enrichment analysis (GSEA) was utilizedto predict the critical pathways underlying radioresistance in OSCC. The colony-forming assay was used to estimatethe consequences of irradiation sensitivity after the inhibition or activation of the NEDD8-autophagy axis in OSCC cells.
Results
NEDD8 upregulation was extensively found in primary tumors compared to normal adjacent tissues andpotentially served as a predictive marker for the therapeutic efectiveness of irradiation in OSCC patients. NEDD8 knockdown enhanced radiosensitivity but NEDD8 overexpression reduced it in OSCC cell lines. The inclusion of MLN4924, a pharmaceutical inhibitor for NEDD8-activating enzyme, dose-dependently restored the cellular sensitivity to irradiation treatment in irradiation-insensitive OSCC cells. Computational simulation by GSEA software and cell based analyses revealed that NEDD8 upregulation suppresses Akt/mTOR activity to initiate autophagy formation andultimately confers radioresistance to OSCC cells.
Conclusion
These fndings not only identify NEDD8 as a valuable biomarker to predict the efcacy of irradiation but also ofer a novel strategy to overcome radioresistance via targeting NEDD8-mediated protein neddylation in OSCC.
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