长链非编码RNA—NR_027005通过负调控miR-1促进胆囊癌的发生发展

The prognosis of gallbladder cancer patients is extremely poor because of the metastasis after surgery and the lack of effective molecular targets. Recently, increasing evidence indicates that lncRNAs(long non-coding RNA) play important roles in the regulation of gene expression through epigenetic, transcriptional and post-transcriptionallevel. In this study, we found that the lncRNA High expression in GallbladderCancer (lncRNA-HGBC) was aberrantly upregulated in gallbladder cancer through our lncRNA microarray data. In our previous research, we demonstrated that lncRNA-HGBC could promote the proliferative and metastatic capability of gallbladder cancer cells. Furthermore, we found that downregulation of lncRNA-HGBC could attenuate the expression of VEGFA, LASP1 and MET, which are reported to be oncogenes targeted by miR-1. Therefore, we hypothesize that lncRNA-HGBC promotes gallbladder cancer development via negative regulation of miR-1. In this project, we plan to systematically investigate the interaction between lncRNA-HGBC, miR-1 and the target genes of miR-1. Moreover, we will identify the downstream signaling pathways modulated by lncRNA-HGBC. Our research will provide new strategies and targets for the diagnosis and treatment of gallbladder cancer.

胆囊癌的预后差且容易发生转移，临床上缺乏有效的分子靶点。近年来，越来越多的文献证实l长脸非编码RNA(lncRNA)在癌症中的关键调控作用。我们通过lncRNA表达谱芯片筛选到一条在胆囊癌中异常高表达的lncRNA，我们将其命名为lncRNA-HGBC。我们的前期工作证实lncRNA-HGBC可以促进胆囊癌细胞的增殖和转移能力，lncRNA-HGBC沉默后的mRNA芯片结果显示lncRNA-HGBC的沉默能够下调潜在的致癌基因VEGFA、LASP1及MET的表达水平，而这三个基因都是miR-1的靶基因。因此我们猜测lncRNA-HGBC可能通过负调控miR-1来促进胆囊癌的发生发展。在本项目中，我们将系统研究lncRNA-HGBC、miR-1及其靶基因之间的相互作用关系，鉴定并筛选lncRNA-HGBC影响的下游信号通路。本项目研究结果将为胆囊癌的诊断和进一步治疗提供崭新思路和靶标。

胆囊癌是最常见的胆道系统恶性肿瘤且预后极差，长链非编码RNA（lncRNA）在肿瘤的发生发展起重要调控作用。本研究通过胆囊癌及癌旁组织的表达谱芯片分析，发现胆囊癌预后相关的新长链非编码lncRNA-HGBC。胆囊癌组织中lncRNA-HGBC异常高表达，且与胆囊癌患者的临床分期及淋巴结转移相关，高表达提示预后更差。生物信息学分析及体外翻译实验结果表明lncRNA-HGBC不具备编码蛋白的能力。细胞功能学研究表明lncRNA-HGBC在体外促进胆囊癌细胞的增殖及转移能力。裸鼠皮下成瘤实验和小鼠肝转移实验表明lncRNA-HGBC在体内促进胆囊癌细胞的增殖及转移。利用RNA pulldown结合质谱技术发现 lncRNA-HGBC与RNA结合蛋白（RNA Binding Protein）HuR结合，这种结合可以提高lncRNA-HGBC的稳定性。lncRNA-HGBC通过竞争性结合miR-502-3p从而解除了miR-502-3p对SET的抑制作用，使得SET的表达上调，进而激活AKT信号通路，最终促进胆囊癌细胞的增殖及侵袭转移。本研究为胆囊癌预后相关的生物标志物发现和药理学调控靶点提供新的科学依据。