Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
Department of Radio-chemotherapy, Shangrao People's Hospital, Shangrao, Jiangxi, China.
Cell Death Dis. 2017 Jun 15;8(6):e2874. doi: 10.1038/cddis.2017.271.
Concurrent/adjuvant cisplatin-based chemoradiotherapy is regarded as the standard of treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, patients who do not respond to cisplatin suffer, rather than benefit, from chemotherapy treatment. The goal of this study was to identify molecules involved in cisplatin resistance and to clarify their molecular mechanisms, which would help in the discovery of potential therapeutic targets and in developing a personalized and precise treatment approach for NPC patients. We previously generated a cisplatin-sensitive NPC cell line, S16, from CNE2 cells and found that eIF3a, ASNS and MMP19 are upregulated in S16 cells, which contributes to their cisplatin sensitivity. In this study, we found that BST2 is downregulated in cisplatin-sensitive S16 cells compared with CNE2 cells. Knockdown of BST2 in NPC cells sensitized their response to cisplatin and promoted cisplatin-induced apoptosis, whereas exogenous overexpression of BST2 increased their cisplatin resistance and inhibited cisplatin-induced apoptosis. Further investigation demonstrated that BST2-mediated cisplatin resistance depended on the activation of the NF-κB signaling pathway and consequent upregulation of anti-apoptotic genes, such as Bcl-X and livin. Moreover, an analysis of clinical data revealed that a high BST2 level might serve as an independent indicator of poor prognosis in patients with locally advanced NPC treated with platinum-based chemoradiotherapy. These findings suggest that BST2 likely mediates platinum resistance in NPC, offering guidance for personalized and precise treatment strategies for patients with NPC.
顺铂为基础的放化疗联合治疗被认为是局部晚期鼻咽癌（NPC）的标准治疗方法。然而，对顺铂不敏感的患者从化疗治疗中受益，而不是受益。本研究的目的是确定与顺铂耐药相关的分子，并阐明其分子机制，这将有助于发现潜在的治疗靶点，并为 NPC 患者制定个性化和精确的治疗方法。我们之前从 CNE2 细胞中生成了顺铂敏感的 NPC 细胞系 S16，并发现 eIF3a、ASNS 和 MMP19 在 S16 细胞中上调，这有助于它们对顺铂的敏感性。在这项研究中，我们发现 BST2 在顺铂敏感的 S16 细胞中比 CNE2 细胞中下调。NPC 细胞中 BST2 的敲低使它们对顺铂的反应敏感，并促进顺铂诱导的细胞凋亡，而 BST2 的外源性过表达增加了它们对顺铂的耐药性并抑制了顺铂诱导的细胞凋亡。进一步的研究表明，BST2 介导的顺铂耐药取决于 NF-κB 信号通路的激活以及抗凋亡基因如 Bcl-X 和 livin 的上调。此外，临床数据分析表明，高 BST2 水平可能是接受铂类化疗联合放疗的局部晚期 NPC 患者预后不良的独立指标。这些发现表明，BST2 可能在 NPC 中介导铂类耐药，为 NPC 患者的个性化和精确治疗策略提供指导。
