MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma
MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma
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MicroRNA-18a 通过 SMG1 抑制和 mTOR 通路激活促进鼻咽癌的癌症进展
DOI：
10.1038/s41419-019-2060-9
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发表时间：
2019-10-28
影响因子：
9
通讯作者：
Wang, HuiYun
中科院分区：
文献类型：
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作者：
Mai, ShiJuan;Xiao, RuoWen;Wang, HuiYun
有报道称，通过基因芯片技术，mir-18a在鼻咽癌组织中表达上调。然而，miR-18a在鼻咽癌中的作用和潜在机制仍然知之甚少。在这里，我们通过实时荧光RT-PCR证实miR-18a在鼻咽癌组织中表达上调，并与肿瘤大小和TNM分期呈正相关。此外，NF-kappa B的激活或EB病毒编码的潜伏膜蛋白1的表达可上调miR-18a的表达。MiR-18a的异位表达促进了鼻咽癌细胞的增殖、迁移和侵袭，而抑制miR-18a的作用则相反。通过全基因组微阵列分析筛选出miR-18a调控下的候选基因，通过报告实验进一步鉴定，并在临床样本中进行验证。SMG1是肌醇磷脂3-激酶相关蛋白家族的成员，是mTOR拮抗剂，被认为是miR-18a的功能靶点。我们的结果证实miR-18a在鼻咽癌细胞中通过抑制SMG1和激活mTOR通路发挥其致癌作用。重要的是，瘤内注射miR-18a能有效地抑制裸鼠体内移植瘤的生长。我们的数据支持miR-18a通过一个新的miR-18a/SMG1/mTOR轴发挥致癌作用，并提示antagomir-18a的抗肿瘤作用可能使其适合于鼻咽癌治疗。
miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-kappa B activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.