The Homologous Recombination Repair Pathway is Associated with Resistance to Radiotherapy in Nasopharyngeal Carcinoma
The Homologous Recombination Repair Pathway is Associated with Resistance to Radiotherapy in Nasopharyngeal Carcinoma
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同源重组修复途径与鼻咽癌放疗耐药相关
DOI：
10.7150/ijbs.37302
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发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
Hu, Guohua
中科院分区：
文献类型：
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作者：
Wang, Zhihai;Zuo, Wenqi;Hu, Guohua
放射治疗在鼻咽癌（NPC）的治疗中发挥着重要作用。然而，抗辐射细胞限制了其效率并导致受辐射肿瘤体积内的复发，导致患者预后不佳。为了阐明放射抗性涉及的信号通路并评估预测NPC对放疗反应的潜力，我们通过逐渐增加辐射剂量（总计60 Gy）从NPC细胞系CNE2建立了抗辐射NPC细胞系（CNE2-RR），并通过集落形成、FCM和彗星实验评估CNE2-RR细胞的放射抗性。此外，将已建立的 CNE2-RR 细胞系与亲本细胞系进行比较，发现同源重组修复 (HRR) 蛋白差异与 NPC 放射抗性有关。此外，通过免疫印迹、免疫荧光和 IHC 在肿瘤异种移植物和抗辐射的鼻咽癌组织中进一步验证了差异表达的蛋白。此外，还评估了HRR蛋白表达水平与NPC放射抗性的相关性。结果表明HRR蛋白的上调与NPC放射抵抗显着相关。此外，使用约登指数截止值，一组 HRR 蛋白分析显示敏感性为 70%，特异性为 72%。此外，沉默 NFBD1 通过损害 IR 诱导的 γ-H2AX 和 HR 蛋白病灶形成来增强 CNE2-RR 细胞的放射敏感性。这些结果表明，控制 HRR 信号通路可能有望克服 NPC 放射抗性。
Radiotherapy plays a major role in the management of nasopharyngeal carcinoma (NPC). However, the radioresistant cells limit its efficiency and drive recurrence inside the irradiated tumor volume leading to poor outcome for patients. To illuminate the signal pathway involved in the radioresistance and evaluate the potential for predicting NPC response to radiotherapy, we established the radioresistant NPC cell line (CNE2-RR) derived from NPC cell line CNE2 by gradually increased the radiation dose (total 60 Gy), and the radioresistance of CNE2-RR cells was evaluated by the colony formation, FCM and comet assays. Furthermore, comparison of established CNE2-RR cell line to parental cell line found the homologous recombination repair (HRR) proteins differences involved in NPC radioresistance. In addition, the differentially expressed proteins were further validated by western blotting, immunofluorescence and IHC in tumor xenografs and radioresistant NPC tissues. Furthermore, the correlation of HRR proteins expression levels with NPC radioresistance were evaluated. The results showed that the upregulation of HRR proteins were significantly correlated with NPC radioresistance. In addition, using the Youden Index cutoff value, a panel of the HRR proteins analyses revealed a sensitivity of 70%, specificity of 72%. Furthermore, silencing NFBD1 enhanced the radiosensitivity of CNE2-RR cells by impairing IR-inducing γ-H2AX and HR proteins foci formation. These results suggest that controlling the HRR signaling pathway may hold promise to overcome NPC radioresistance.