基于基因芯片及TCGA大数据分析筛选，我们发现miR-449b-3p差异低表达于转移性鼻咽癌，验证显示miR-449b-3p在鼻咽癌组织中低表达，与EB病毒DNA拷贝数、肿瘤分期负相关，与患者预后正相关；过表达miR-449b-3p可抑制细胞增殖、侵袭迁移。预实验发现EB病毒癌蛋白LMP1负调控miR-449b-3p表达，而与肿瘤侵袭转移及不良预后密切相关的ADAM17为miR-449b-3p的下游靶基因。故提出“LMP1通过抑制miR-449b-3p诱导ADAM17表达促进鼻咽癌侵袭转移”的科学假说。本项目拟在体内外水平采用过表达/沉默策略，通过拯救实验、报告基因、RIP-Chip、启动子甲基化等实验，结合临床验证，阐明miR-449b-3p受LMP1调控并通过下游ADAM17参与鼻咽癌侵袭转移的分子机制。本假说的阐明，可为EB病毒与宿主miRNA的相互调控及鼻咽癌防治提供新靶标。

We have identified miR-449b-3p as a metastasis-related non-coding RNA that is frequently downregulated in the nasopharyngeal carcinoma (NPC) tissues using miRNA microarray and TCGA database analyses followed by validation with quantitative PCR. Our preliminary data revealed that downregulation of miR-449b-3p is inversely correlated with EBV-DNA copy number and 2008 TNM stage and is associated with poor prognosis. Overexpression of miR-449b-3p significantly suppressed NPC cell proliferation, invasion and migration. Interestingly, we found that miR-449b-3p expression was inhibited by LMP1, an Epstein-Barr virus-encoded oncoprotein, and that ADAM17, a protein strongly correlated with tumor cell invasion, migration and poor prognosis, is a direct target of miR-449b-3p in NPC cells. Together, our results reveal a novel hypothesis that LMP1 induces ADAM17 expression and promotes NPC cell invasion and migration via suppressing miR-449b-3p. This proposal is designed to further investigate the LMP1/miR-449b-3p/ADAM17 interaction network and its implication in NPC. Multidisciplinary approaches including gain- and loss-of-function analysis in cell and in vivo, rescue experiments, luciferase reporter assays, RIP-chip assays and promoter methylation detection will be performed. Finally, we will comprehensively analyze the clinical correlation between LMP1/miR-449b-3p/ADAM17 axis and NPC progression. Thus, our novel finding would not only provide a molecular insight into how EBV oncoprotein LMP1 interacts with host-miRNA, but also contribute to the development of new biomarker and therapeutic target in NPC.