lncRNA-DANCR在鼻咽癌转移中的作用和分子机制研究

Distant metastasis is a key factor restricting to improve curative effect of nasopharyngeal carcinoma (NPC). Long noncoding RNAs (lncRNAs) has been reported to play important roles in tumor metastatic processes. Our previous study found that: ①lncRNA-DANCR was obviously upregulated in NPC cell lines and tissue samples, and knocking-down of lncRNA-DANCR could inhibit NPC cell migration and invasion; RNA pulldown-mass spectrometry assay found that lncRNA-DANCR could bind with NF45 protein, and silencing lncRNA-DANCR could inhibit NF45 protein expression; the decreased migration ability of the siDANCR NPC cells could be rescued by NF45 overexpression.③in 60 clinical samples, we found that the expression of lncRNA-DANCR was higher in patients with metastasis and it could predict poorer survival. On the basis of the preliminary experiment, we put forward the hypothesis that lncRNA-DANCR promotes NPC metastasis through NF45 and guides individual treatment as a prognostic biomarker. We intend to carry out the following researches: ①study the function and mechanism of lncRNA-DANCR in NPC invasion and metastasis through in vitro and in vivo functional experiments and finding targeted genes; ② examine the expression level of lncRNA-DANCR in 312 NPC clinical samples, to evaluate the predictive value of lncRNA-DANCR in NPC metastasis and prognosis. Through the implementation of this project, it could provide new targets for the treatment of nasopharyngeal carcinoma, and further guide clinical selection of high risk patients for individual treatment.

远处转移是制约鼻咽癌疗效提高的关键原因。lncRNA在肿瘤转移中起重要作用。我们前期发现：①lncRNA-DANCR在鼻咽癌中表达升高，干扰其表达可抑制鼻咽癌细胞的迁移和侵袭；RNA pulldown-质谱分析发现lncRNA-DANCR与NF45蛋白结合，且lncRNA-DANCR调控NF45的表达，回补NF45可促进鼻咽癌细胞的迁移②小样本量分析发现，lncRNA-DANCR在转移鼻咽癌组织中表达升高且提示不良预后。因此我们提出假说: lncRNA-DANCR通过NF45促进鼻咽癌的转移，且作为分子指标，指导个体化治疗。本项目拟开展以下研究：①通过体内外实验及下游靶点的寻找与验证，阐明lncRNA-DANCR在鼻咽癌转移中的功能和机制②检测312例鼻咽癌组织中lncRNA-DANCR表达水平，明确lncRNA-DANCR在鼻咽癌转移和预后中的价值，为发现新靶点和实现个体化治疗奠定基础。

远处转移是鼻咽癌治疗失败的主要原因，只有鉴别出与鼻咽癌转移相关的因素，系统阐明其作用和机制，才能指导临床甄选出高转移风险的患者进行个体化临床治疗，从而达到提高疗效的目的。在本课题的资助下，我们课题组取得了如下成果：①明确了lncRNA-DANCR、FAM225A、TINCR、LINC01503高表达与鼻咽癌患者的不良预后相关，并阐明了它们参与调控鼻咽癌恶性进展的分子机制；②阐明了转移相关基因RAB37被甲基化沉默后促进鼻咽癌转移和化疗抵抗的分子机制，并明确了其可以预测鼻咽癌远处转移风险以及诱导化疗疗效；③揭示了EZH2/DNMT1介导的miR-142-3p甲基化沉默，导致其对下游靶点ZEB2的抑制解除而促进鼻咽癌转移的分子机制；上述研究为鼻咽癌个体化精准治疗提供了分子预后指标和潜在干预靶点。申请人以（共同）通讯作者身份发表SCI收录论文6篇，总IF 75.2，包括Cell Death Differ (IF 15.8)、Cancer Res (IF 12.7)、Clin Cancer Res (IF 12.5)、Theranostics (IF 11.6)、Oncogene (IF 9.9)，获得了2018年度第十一届“吴孟超医学青年基金奖”，并作为主要完成人获得了2019年度“中国高等学校十大科技进展”、2020年度“高等学校科技进步一等奖”和2020年度“广东医学科技一等奖”。