lnc-BCL2L11通过METTL14调控MAP2甲基化促进胆囊癌侵袭转移的机制研究

胆囊癌是胆道系统最常见的恶性肿瘤，预后极差且极易发生侵袭转移。长链非编码RNA（lncRNA）在胆囊癌侵袭转移中的作用仍不清楚。我们前期从临床样本和动物模型两方面入手，利用表达谱芯片筛选出胆囊癌侵袭转移相关lncRNA：lnc-BCL2L11；进一步研究发现，lnc-BCL2L11在胆囊癌组织中高表达，能够促进胆囊癌的侵袭转移，且与病人预后相关；lnc-BCL2L11通过与METTL14蛋白相互结合增加其在细胞核中的分布，提高MAP2的RNA甲基化水平，降低MAP2蛋白表达，从而促进胆囊癌侵袭转移。在本项目中，我们要明确：(1)lnc-BCL2L11对胆囊癌细胞侵袭转移的作用；(2) lnc-BCL2L11通过与METTL14结合调控MAP2甲基化促进胆囊癌侵袭转移的详细机制；(3) lnc-BCL2L11作为胆囊癌侵袭转移标志物及治疗靶点的可行性。

Gallbladder cancer(GBC) is the most common cancer of the biliary tract with poor prognosis. Liver invasion and metastasis often occur in GBC patients. Long noncoding RNAs(lncRNAs) play important roles in the carcinogenesis and development of many cancers. While the role of lncRNAs in the invasion and metastasis of GBC is still unclear. In order to find out lncRNAs that participated in the invasion and metastasis of GBC, we began expression microarray scanning from the aspects of clinical specimens and animal models, and finally focused on lnc-BCL2L11. Our results showed that lnc-BCL2L11 was highly expressed in GBC tissues compared with adjacent non-tumor tissues. lnc-BCL2L11 could promote the invasion and migration ability of GBC cells in vitro and predict prognosis of GBC patients. Mechanistically, we found that lnc-BCL2L11 could bind to the protein of METTL14 and increase its nuclear distribution，thus promote the RNA methylation of MAP2 and decrease the expression of MAP2 protein, and finally promote the invasion and metastasis of GBC. In this project, we will accomplish the following items: (1) clarify the role of lnc-BCL2L11 in the invasion and metastasis processes of GBC；(2) reveal the underlying molecular mechanisms that lnc-BCL2L11 regulate the m6A RNA methylation of MAP2 through binding to METTL14; (3) explore the possibility that if lnc-BCL2L11 could serve as the diagnostic marker and therapeutic target of GBC.