lincRNA L-NPC募集hnRNP K抑制鼻咽癌演进的分子机制研究

The function and the mechanism of lincRNAs in nasopharyngeal carcinoma (NPC) are still unclear. In our previous studies, we identified differentially expressed lincRNAs in nasopharyngeal carcinoma tissues using microarray analysis. Our results showed that lincRNA L-NPC may act as a tumor suppresser gene in nasopharyngeal carcinoma. We further found that lincRNA L-NPC could combine with hnRNP K(a member of heterogeneous nuclear ribonucleoproteins) and modulate the change of transcription variants of the CTNND1 gene. In addition, bioinformatics analysis showed that both the pre-mRNA of CTNND1 and lincRNA L-NPC contained sequences complementing to each other. Therefore, we hypothesize that lincRNA L-NPC may be guided by the complementary sequences to regulate the alternative splicing of pre-mRNA of target genes and affect signal pathways through recruiting hnRNP K, thus inhibiting the occurrence and progression of nasopharyngeal carcinoma. In this study, we will perform experiments in vitro and in vivo to gain the proof that lincRNA L-NPC can lead hnRNP K to regulate the alternative splicing of pre-mRNA through combining with the complementary sequences of the pre-mRNA of CTNND1. What’s more, this study will provide theoretical evidence for the relationship between lincRNA L-NPC and prognosis of nasopharyngeal carcinoma patients. Success of this study will provide original scientific basis for lincRNA L-NPC acting as novel biomarker and candidate therapeutic target in nasopharyngeal carcinoma.

长链基因间非编码RNA（lincRNAs）在鼻咽癌的作用机制尚未阐明。我们通过基因芯片鉴定出鼻咽癌中起抑癌基因作用的lincRNA L-NPC，初步证实其与异质性核糖蛋白hnRNPK结合，并介导CTNND1基因的剪接体转换，生物信息学分析提示CTNND1的mRNA前体与lincRNA L-NPC存在互补序列。由此，我们提出科学假说：lincRNA L-NPC通过与靶基因mRNA前体的互补序列结合，募集hnRNPK到mRNA前体上发挥剪接功能，调控pre-mRNA的可变剪接，影响下游信号通路活性进而抑制鼻咽癌演进。本研究拟进一步采用体内外实验获得lincRNA L-NPC与CTNND1 mRNA前体序列互补结合，引导hnRNPK调控CTNND1 pre-mRNA选择性剪接的可靠证据，明确lincRNA L-NPC与患者预后的关系，为lincRNA L-NPC作为鼻咽癌诊治新靶点提供科学依据。

本项目按研究计划执行。我们通过基因芯片鉴定出鼻咽癌中起抑癌基因作用的lincRNA L-NPC，通过细胞功能实验证实lincRNA L-NPC在鼻咽癌细胞中发挥着抑制增殖、迁移及促进细胞凋亡的作用，同时裸鼠皮下成瘤模型也发现lincRNA L-NPC抑制鼻咽癌细胞增殖。分子机制研究方面我们证实了lincRNA L-NPC通过与CTNND1等靶基因mRNA前体的互补序列结合，募集hnRNPK到mRNA前体上发挥剪接功能，调控pre-mRNA的可变剪接进而抑制鼻咽癌演进。我们在扩大样本的队列中证明了LincRNA L-NPC的表达量与鼻咽癌患者的预后密切相关，有望成为判断鼻咽癌患者预后的分子指标。