Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 33302, Taiwan.
Cells. 2022 May 7;11(9):1581. doi: 10.3390/cells11091581.
N-Myc downstream-regulated 1 (NDRG1) has inconsistent oncogenic functions in various cancers. We surveyed and characterized the role of NDRG1 in head and neck cancer (HNC). Cellular methods included spheroid cell formation, clonogenic survival, cell viability, and Matrigel invasion assays. Molecular techniques included transcriptomic profiling, RT-qPCR, immunoblotting, in vitro phosphorylation, immunofluorescent staining, and confocal microscopy. Prognostic significance was assessed by Kaplan-Meier analysis. NDRG1 participated in diverse oncogenic functions in HNC cells, mainly stress response and cell motility. Notably, NDRG1 contributed to spheroid cell growth, radio-chemoresistance, and upregulation of stemness-related markers (CD44 and Twist1). NDRG1 facilitated cell migration and invasion, and was associated with modulation of the extracellular matrix molecules (fibronectin, vimentin). Characterizing the 3R-motif in NDRG1 revealed its mechanism in the differential regulation of the phenotypes. The 3R-motif displayed minimal effect on cancer stemness but was crucial for cell motility. Phosphorylating the motif by GSK3b at serine residues led to its nuclear translocation to promote motility. Clinical analyses supported the oncogenic function of NDRG1, which was overexpressed in HNC and associated with poor prognosis. The data elucidate the multifaceted and intricate mechanisms of NDRG1 in HNC. NDRG1 may be a prognostic indicator or therapeutic target for refractory HNC.
N- MYC 下游调节因子 1（NDRG1）在各种癌症中的致癌功能不一致。我们调查并描述了 NDRG1 在头颈部癌症（HNC）中的作用。细胞方法包括球体细胞形成、集落形成存活、细胞活力和基质胶侵袭测定。分子技术包括转录组谱分析、RT-qPCR、免疫印迹、体外磷酸化、免疫荧光染色和共聚焦显微镜。通过 Kaplan-Meier 分析评估预后意义。NDRG1 参与了 HNC 细胞中的多种致癌功能，主要是应激反应和细胞迁移。值得注意的是，NDRG1 促进了球体细胞生长、放射化学抗性和干性相关标志物（CD44 和 Twist1）的上调。NDRG1 促进了细胞迁移和侵袭，并与细胞外基质分子（纤连蛋白、波形蛋白）的调节有关。对 NDRG1 的 3R 基序进行特征分析揭示了其在表型差异调节中的机制。3R 基序对癌症干性的影响最小，但对细胞迁移至关重要。GSK3b 在丝氨酸残基上对基序进行磷酸化导致其核易位以促进迁移。临床分析支持 NDRG1 的致癌功能，NDRG1 在 HNC 中过度表达，并与预后不良相关。这些数据阐明了 NDRG1 在 HNC 中的多方面和复杂机制。NDRG1 可能是难治性 HNC 的预后指标或治疗靶点。
