Department of Pathology, The Second Affiliated Hospital, Guilin Medical University, Guilin, China.
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
J Cell Mol Med. 2020 Jun;24(11):6438-6447. doi: 10.1111/jcmm.15291. Epub 2020 Apr 19.
Cisplatin resistance is one of the main obstacles in the treatment of advanced nasopharyngeal carcinoma (NPC). AKR1C1 is a member of the Aldo-keto reductase superfamily (AKRs), which converts aldehydes and ketones to their corresponding alcohols and has been reported to be involved in chemotherapeutic resistance of multiple drugs. The expression and function of AKR1C1 in NPC have not been reported until now. The aim of this research was to investigate the expression of AKR1C1 and it is role in cisplatin resistance in NPC. AKR1C1 protein expression was detected by immunohistochemistry in human NPC tissues and by Western blot assays in NPC and immortalized nasopharyngeal epithelial cells. The effects of AKR1C1 knock-down by siRNA on proliferation, migration and invasion in NPC cells were evaluated by CCK8, wound healing and transwell assays. To evaluate the effects of AKR1C1 silencing on cisplatin sensitivity in NPC cells, CCK8 assays were used to detect cell proliferation, flow cytometry was used to detect cell cycle distribution, and flow cytometry and DAPI staining were used to detect cell apoptosis. AKR1C1 down-regulation was associated with advanced clinicopathological characters such as larger tumor size, more lymphatic nodes involvement, with metastasis and later clinical stages, while AKR1C1 down-regulation was a good prognostic factor for overall survival (OS) in NPC patients. In vitro study showed that AKR1C1 was not directly involved in the malignant biological behaviours such as proliferation, cell cycle progression and migration of NPC cells, whereas AKR1C1 knock-down could enhance cisplatin sensitivity of NPC cells. These results suggest that AKR1C1 is a potential marker for predicting cisplatin response and could serve as a molecular target to increase cisplatin sensitivity in NPC.
顺铂耐药是治疗晚期鼻咽癌（NPC）的主要障碍之一。AKR1C1 是醛酮还原酶超家族（AKR）的成员，可将醛和酮转化为相应的醇，并且据报道参与多种药物的化疗耐药。到目前为止，AKR1C1 在 NPC 中的表达和功能尚未报道。本研究旨在研究 AKR1C1 的表达及其在 NPC 顺铂耐药中的作用。通过免疫组织化学检测人 NPC 组织中 AKR1C1 蛋白的表达，通过 Western blot 检测 NPC 和永生化鼻咽上皮细胞中 AKR1C1 的表达。通过 CCK8、划痕愈合和 Transwell 测定评估 AKR1C1 siRNA 敲低对 NPC 细胞增殖、迁移和侵袭的影响。为评估 AKR1C1 沉默对 NPC 细胞顺铂敏感性的影响，采用 CCK8 测定检测细胞增殖，采用流式细胞术检测细胞周期分布，采用流式细胞术和 DAPI 染色检测细胞凋亡。AKR1C1 下调与较大的肿瘤大小、更多的淋巴结受累、转移和较晚的临床分期等较晚期的临床病理特征相关，而 AKR1C1 下调是 NPC 患者总生存（OS）的良好预后因素。体外研究表明，AKR1C1 不直接参与 NPC 细胞的恶性生物学行为，如增殖、细胞周期进展和迁移，而 AKR1C1 敲低可增强 NPC 细胞对顺铂的敏感性。这些结果表明，AKR1C1 是预测顺铂反应的潜在标志物，并可作为增加 NPC 中顺铂敏感性的分子靶标。
