Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China.
The Fourth Clinical School of Nanjing Medical University, Nanjing, China.
Cancer Med. 2019 Oct;8(13):6049-6063. doi: 10.1002/cam4.2469. Epub 2019 Aug 21.
An emerging body of evidence has promoted the understanding of the role of microRNAs (miRNAs) in tumorigenesis and progression, but the mediating function of miRNAs in nasopharyngeal carcinoma (NPC) development remains poorly elucidated. In this study, miR-449b-3p was downregulated in NPC specimens (P < .001) and cells (P < .05). Cytological and animal experiments provided evidence that miR-449b-3p inhibited NPC metastasis in vitro and in vivo. Disintegrin and metalloproteinase 17 (ADAM17) was revealed as a direct target of miR-449b-3p. Rescue experiments suggested that the downregulation of ADAM17 in the miR-449b-3p knockdown cells partially reversed the inhibition of cell invasion and migration. Luciferase reporter assay, chromatin immunoprecipitation assay, and Western blot analysis showed that ADAM17 could suppress the promoter activity and expression of miR-449b-3p by inducing NF-κB transcriptional activity. In conclusion, our study provided new insights into the underlying mechanism of the invasion and metastasis of NPC. The novel miR-449b-3p/ADAM17/NF-κB feedback loop could be a target for the clinical treatment of NPC.
越来越多的证据表明 microRNAs（miRNAs）在肿瘤发生和进展中的作用，但 miRNA 在鼻咽癌（NPC）发展中的介导功能仍未得到充分阐明。在这项研究中，miR-449b-3p 在 NPC 标本（P<.001）和细胞（P<.05）中下调。细胞学和动物实验提供的证据表明，miR-449b-3p 抑制 NPC 的体外和体内转移。解整合素金属蛋白酶 17（ADAM17）被揭示为 miR-449b-3p 的直接靶标。挽救实验表明，miR-449b-3p 敲低细胞中 ADAM17 的下调部分逆转了细胞侵袭和迁移的抑制。荧光素酶报告基因检测、染色质免疫沉淀检测和 Western blot 分析表明，ADAM17 可以通过诱导 NF-κB 转录活性来抑制 miR-449b-3p 的启动子活性和表达。总之，我们的研究为 NPC 侵袭和转移的潜在机制提供了新的见解。新型 miR-449b-3p/ADAM17/NF-κB 反馈环可能成为 NPC 临床治疗的靶点。
