超级lncRNA SUCLG2-AS1促进鼻咽癌侵袭及转移的机制研究

Super-lncRNAs are novel lncRNAs that were transcribed from the super-enhancers (SEs) region.Based on RNA-sequencing and super-lncRNA database analysis, we have identified SUCLG2-AS1 (SU) as a significantly up-regulated super-lncRNA with unknown function in metastatic nasopharyngeal carcinoma (NPC). Our pre-experiments demonstrated that the high expression of SU was notably associated with N stage and poor prognosis of NPC. The invasion and migration of NPC cells decreased after SU silencing. Moreover, bioinformatics combined with preliminary studies suggested that SU was located in SEs region of SOX2 and both SEs of SOX2 and promoter region were rich in the binding sites of transcription factor CTCF. RIP experiments confirmed that SU bound to CTCF. Therefore, we hypothesize that the super-lncRNA SU transcribed from the SEs of SOX2 may mediate the SEs of SOX2 binding to the promoter to form the CTCF-CTCF circular domain by raising the CTCF.This process will active the transcription of SOX2 and other target genes to promote the invasion and metastasis of NPC. The project intends to expand the clinical samples and the hypothesis will be deeply validated by relevant experiments, thus enriching the molecular mechanism of invasion and metastasis of NPC. Our study may provide new targets for the diagnosis and treatment of NPC.

超级lncRNA是由超级增强子（SEs)区域转录的新型lncRNA。SUCLG2-AS1（简称SU）是本课题组通过转录组测序结合超级lncRNA数据库分析筛选的一条差异高表达于人转移性鼻咽癌组织、功能未知的超级lncRNA。预实验提示：SU高表达与鼻咽癌N分期及不良预后显著相关；沉默SU后鼻咽癌细胞的侵袭迁移能力下降；生物信息学分析结合预实验提示SU位于SOX2的SEs区域，SOX2的SEs和启动子区域富集CTCF结合位点，RIP实验证实SU绑定CTCF。故我们提出以下科学假说：由SOX2的SEs转录的超级lncRNA SU可能通过绑定CTCF，介导SOX2的SEs与启动子区域结合形成CTCF-CTCF环形结构域，从而远程增强SOX2及更多潜在靶基因的转录激活，进而促进鼻咽癌的侵袭转移。本课题组将扩大临床样本，并用相关技术证实上述假说，丰富鼻咽癌侵袭转移的分子机制，为鼻咽癌诊治提供新靶标。

超级lncRNA是由超级增强子（SEs）区域转录的新型lncRNA。SUCLG2-AS1是本课题组通过转录组测序结合超级lncRNA数据库分析筛选的一条差异高表达于人转移性鼻咽癌组织、功能未知的超级lncRNA。研究中我们发现SUCLG2-AS1的高表达与鼻咽癌N分期及不良预后显著相关；体内及体外研究证实了SUCLG2-AS1可以调节鼻咽癌细胞的侵袭、转移、凋亡及放射敏感性。结合生物信息学及表达机制验证实验，证实了SUCLG2-AS1定位于SOX2的SEs区域，SUCLG2-AS1通过绑定CTCF（转录因子）形成长程染色质环，介导SOX2的SEs与启动子区域结合，从而远程增强SOX2的转录激活，进而调节鼻咽癌的侵袭转移和放射敏感性。本研究的成功实施为鼻咽癌侵袭转移及放射敏感性的调控机制提供新的线索，SUCLG2-AS1可能成为鼻咽癌临床治疗中新的干预靶点。