Yuan Tsu-Zong, Lin Hui-Yu, Kuei Chia-Hao, Lin Che-Hsuan, Lee Hsun-Hua, Lee Hsin-Lun, Lu Hsiao-Wei, Su Chia-Yi, Chiu Hui-Wen, Lin Yuan-Feng
Department of Radiation Oncology, Yuan's General Hospital, Kaohsiung, 802, Taiwan.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
Cancer Cell Int. 2023 Mar 8;23(1):41. doi: 10.1186/s12935-023-02883-0.
Radiotherapy is the first-line regimen for treating oral squamous cell carcinoma (OSCC) in current clinics. However, the development of therapeutic resistance impacts the anticancer efficacy of irradiation in a subpopulation of OSCC patients. As a result, discovering a valuable biomarker to predict radiotherapeutic effectiveness and uncovering the molecular mechanism for radioresistance are clinical issues in OSCC.
Three OSCC cohorts from The Cancer Genome Atlas (TCGA), GSE42743 dataset and Taipei Medical University Biobank were enrolled to examine the transcriptional levels and prognostic significance of neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8). Gene set enrichment analysis (GSEA) was utilized to predict the critical pathways underlying radioresistance in OSCC. The colony-forming assay was used to estimate the consequences of irradiation sensitivity after the inhibition or activation of the NEDD8-autophagy axis in OSCC cells.
NEDD8 upregulation was extensively found in primary tumors compared to normal adjacent tissues and potentially served as a predictive marker for the therapeutic effectiveness 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 and ultimately confers radioresistance to OSCC cells.
These findings not only identify NEDD8 as a valuable biomarker to predict the efficacy of irradiation but also offer a novel strategy to overcome radioresistance via targeting NEDD8-mediated protein neddylation in OSCC.
放射治疗是目前临床治疗口腔鳞状细胞癌（OSCC）的一线方案。然而，治疗抵抗的出现影响了部分OSCC患者放疗的抗癌疗效。因此，寻找一个有价值的生物标志物来预测放射治疗效果并揭示放射抵抗的分子机制是OSCC的临床问题。
纳入来自癌症基因组图谱（TCGA）的三个OSCC队列、GSE42743数据集和台北医学大学生物样本库，以检测神经元前体细胞表达的发育下调蛋白8（NEDD8）的转录水平和预后意义。采用基因集富集分析（GSEA）预测OSCC放射抵抗的关键通路。采用集落形成试验评估OSCC细胞中NEDD8-自噬轴抑制或激活后照射敏感性的变化。
与相邻正常组织相比，原发性肿瘤中广泛存在NEDD8上调，其可能作为OSCC患者放射治疗效果的预测标志物。在OSCC细胞系中，NEDD8敲低增强放射敏感性，而NEDD8过表达降低放射敏感性。NEDD8激活酶的药物抑制剂MLN4924能剂量依赖性地恢复放射不敏感的OSCC细胞对放射治疗的细胞敏感性。GSEA软件的计算模拟和基于细胞的分析表明，NEDD8上调抑制Akt/mTOR活性，启动自噬形成，最终赋予OSCC细胞放射抗性。
这些发现不仅确定NEDD8是预测放射治疗疗效的有价值生物标志物，还为通过靶向OSCC中NEDD8介导的蛋白质NEDD化来克服放射抵抗提供了新策略。
