Translational Medicine Institute, the First People's Hospital of Chenzhou, University of South China, Hunan 432000, P.R China.
The First School of Clinical Medicine, Southern Medical University, Guangdong Guangzhou 51000, China.
Int J Biol Sci. 2021 Feb 3;17(3):756-767. doi: 10.7150/ijbs.52927. eCollection 2021.
Nasopharyngeal carcinoma (NPC) is one kind of human head and neck cancers with high incidence in Southern China, Southeast Asia and North Africa. In spite of great innovations in radiation and chemotherapy treatments, the 5-year survival rate is not satisfactory. One of the main reasons is resistance to radiotherapy which leads to therapy failure and recurrence of NPC. The mechanism underlying remains to be fully elucidated. Aldo-keto reductase B10 (AKR1B10) plays a role in the formation and development of carcinomas. However, its role in resistance to radiotherapy of NPC is not clear. In this research, the relationships between AKR1B10 expression and the treatment effect of NPC patients, NPC cell survival, cell apoptosis, and DNA damage repair, as well as the effect and mechanism of AKR1B10 expression on NPC radioresistance were explored. A total of 58 paraffin tissues of NPC patients received radiotherapy were collected including 30 patients with radiosensitivity and 28 patients with radioresistance. The relationships between AKR1B10 expression and the treatment effect as well as clinical characteristics were analyzed by immuno-histochemical experiments, and the roles of AKR1B10 in cell survival, apoptosis and DNA damage repair were detected using the AKR1B10 overexpressed cell models. Furthermore the mechanism of AKR1B10 in NPC radioresistance was explored. Finally, the radioresistance effect of AKR1B10 expression was evaluated by the tumor xenograft model of nude mice and the method of radiotherapy. The results showed AKR1B10 expression level was correlated with radiotherapy resistance, and AKR1B10 overexpression promoted proliferation of NPC cells, reduced apoptosis and decreased cellular DNA damage after radiotherapy. The probable molecular mechanism is that AKR1B10 expression activated FFA/TLR4/NF-κB axis in NPC cells. This was validated by using the TLR4 inhibitor TAK242 to treat NPC cells with AKR1B10 expression, which reduced the phosphorylation of NF-κB. This study suggests that AKR1B10 can induce radiotherapy resistance and promote cell survival via FFA/TLR4/NF-κB axis in NPC, which may provide a novel target to fight against radiotherapy resistance of NPC.
鼻咽癌（NPC）是一种在华南、东南亚和北非地区发病率较高的人类头颈部癌症。尽管在放射和化疗治疗方面有了很大的创新，但 5 年生存率仍不尽如人意。其中一个主要原因是对放射治疗的耐药性，这导致 NPC 的治疗失败和复发。其潜在机制仍有待充分阐明。醛酮还原酶 B10（AKR1B10）在癌症的形成和发展中发挥作用。然而，其在 NPC 放射抵抗中的作用尚不清楚。在这项研究中，探讨了 AKR1B10 表达与 NPC 患者治疗效果、NPC 细胞存活、细胞凋亡和 DNA 损伤修复之间的关系，以及 AKR1B10 表达对 NPC 放射抵抗的作用和机制。共收集了 58 例接受放射治疗的 NPC 患者的石蜡组织，包括 30 例放射敏感患者和 28 例放射抵抗患者。通过免疫组织化学实验分析 AKR1B10 表达与治疗效果及临床特征的关系，利用 AKR1B10 过表达细胞模型检测 AKR1B10 在细胞存活、凋亡和 DNA 损伤修复中的作用。进一步探讨 AKR1B10 在 NPC 放射抵抗中的作用机制。最后，通过裸鼠肿瘤异种移植模型和放射治疗方法评估 AKR1B10 表达的放射抵抗效应。结果表明，AKR1B10 表达水平与放射抵抗相关，AKR1B10 过表达促进 NPC 细胞增殖，减少放射后细胞凋亡和降低细胞 DNA 损伤。可能的分子机制是 AKR1B10 表达激活 NPC 细胞中的 FFA/TLR4/NF-κB 轴。这通过使用 TLR4 抑制剂 TAK242 处理 AKR1B10 表达的 NPC 细胞得到验证，该抑制剂降低了 NF-κB 的磷酸化。这项研究表明，AKR1B10 可以通过 FFA/TLR4/NF-κB 轴诱导 NPC 放射抵抗并促进细胞存活，这可能为对抗 NPC 放射抵抗提供新的靶点。
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