Zhang Meng-Xia, Wang Li, Zeng Lei, Tu Zi-Wei
State Key Laboratory of Oncology in South China, Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Department of Radiotherapy, Eye & ENT Hospital, Fudan University, Shanghai, China.
Front Oncol. 2021 Feb 2;10:605777. doi: 10.3389/fonc.2020.605777. eCollection 2020.
Radioresistance-induced local failure, which can result in residual or recurrent tumors, remains one of the major causes of treatment failure in nasopharyngeal carcinoma (NPC). Lipocalin 2 (LCN2) is known to play important roles in cancer initiation, progression, and treatment responses. However, its role in the radioresistance of NPC remains unclear.
Microarray data from the Gene Expression Omnibus (GEO) was screened for candidate biomarkers relating to the radioresistance of NPC. The expression of LCN2 in NPC cell lines was verified by quantitative real-time PCR (RT-qPCR) and western blotting. The effects of knockdown or overexpression of LCN2 on NPC radiosensitivity were examined using a soft agar colony formation assay and a H2AX assay. LCN2 expression in NPC specimens was evaluated by immunohistochemistry. Survival outcomes were analyzed. A possible correlation between LCN2 and hypoxia-inducible factor 1-alpha (HIF-1A) was examined by western blotting and a tissue microarray.
LCN2 was highly expressed in the radioresistant NPC cell line CNE2R. Knocking down LCN2 enhanced the radiosensitivity of NPC cells by impairing their ability to repair DNA damage or proliferate, while ectopic expression of LCN2 conferred additional radioresistance to NPC cells. Immunohistochemical analysis of 100 NPC specimens revealed that LCN2 expression was significantly upregulated in radioresistant NPC tissues and was associated with NPC recurrence. Furthermore, a significant correlation between the expression of LCN2 and HIF-1A was detected.
LCN2 is associated with radioresistance and recurrence in NPC and may facilitate the development of a radioresistant phenotype through interacting with HIF-1A. Our data indicate that LCN2 is a promising target for predicting and overcoming radioresistance in NPC.
放射抗性导致的局部失败可导致残留或复发性肿瘤，仍是鼻咽癌（NPC）治疗失败的主要原因之一。已知脂质运载蛋白2（LCN2）在癌症的发生、发展及治疗反应中发挥重要作用。然而，其在NPC放射抗性中的作用仍不清楚。
从基因表达综合数据库（GEO）筛选与NPC放射抗性相关的候选生物标志物的微阵列数据。通过定量实时PCR（RT-qPCR）和蛋白质印迹法验证NPC细胞系中LCN2的表达。使用软琼脂集落形成试验和H2AX试验检测LCN2敲低或过表达对NPC放射敏感性的影响。通过免疫组织化学评估NPC标本中LCN2的表达。分析生存结果。通过蛋白质印迹法和组织微阵列检测LCN2与缺氧诱导因子1-α（HIF-1A）之间可能的相关性。
LCN2在放射抗性NPC细胞系CNE2R中高表达。敲低LCN2通过损害其修复DNA损伤或增殖的能力增强了NPC细胞的放射敏感性，而LCN2的异位表达赋予NPC细胞额外的放射抗性。对100例NPC标本的免疫组织化学分析显示，LCN2表达在放射抗性NPC组织中显著上调，且与NPC复发相关。此外，检测到LCN2与HIF-1A表达之间存在显著相关性。
LCN2与NPC的放射抗性和复发相关，可能通过与HIF-1A相互作用促进放射抗性表型的形成。我们的数据表明，LCN2是预测和克服NPC放射抗性的一个有前景的靶点。
