LncRNA LINC02027通过SAFA蛋白调控内皮素-1表达并激活YAP/TAZ通路诱导肝细胞癌变的机制研究

肝癌起病隐匿，进展迅速且术后复发率高。寻找并干预与肝癌相关的长链非编码RNA（long non-coding RNA, lncRNA）是治疗肝癌的新思路。我们前期发现lncRNA LINC02027在肝癌中高表达并与患者生存呈负相关，肝癌细胞中LINC02027影响SAFA（scaffold attachment factor A）、内皮素-1表达。本课题将阐述LINC02027促进肝癌发生发展具体机制：（1）肝癌细胞过度表达的LINC02027结合并活化SAFA，使其寡聚化；（2）SAFA寡聚体激活内皮素-1基因增强子，促进其表达分泌；（3）内皮素-1作用于肝细胞内皮素受体A，持续激活胞内YAP（yes associated protein）通路，诱导癌变；（4）肝癌细胞通过下调LINC02027基因启动子CpG岛甲基化水平促进其表达。本课题提出全新的肝癌发生机制，为靶向治疗提供新思路。

Hepatocellular carcinoma (HCC) is a digestive malignant tumor with insidious onset, rapid progression and high postoperative recurrence rate. There has been a new idea for the treatment of HCC by revealing the key long non-coding RNA (lncRNA) highly correlated with HCC and targeting it for intervention. Our previous study showed that lncRNA LINC02027 was significantly up-regulated in HCC, and its expression level was negatively correlated with the long-term survival of HCC patients, suggesting that LINC02027 was closely related to the development of HCC. In addition, LINC02027 could make influence on the expression of SAFA (scaffold attachment factor A) as well as endothelin-1 in HCC cells. Therefore, this subject will systematically elaborate the specific biological function and mechanism of LINC02027 in the development of HCC, including: (1) overexpression of LINC02027 in HCC cells binds and activates SAFA, resulting in oligomerization; (2) SAFA oligomers can activate the enhancer of the endothelin-1 gene, promoting its expression and secretion into the cellular microenvironment; (3) in the microenvironment of liver cancer, endothelin-1 can combine with the endothelin receptor A of hepatocytes and continuously activate the intracellular YAP (yes associated protein) pathway, finally inducing tumorigenesis; (4) HCC cells promoted the expression of LINC02027 by down-regulating the methylation level of LINC02027 gene promoter CpG regions. It has an important theoretical and practical values of this subject in determining new mechanisms of tumorigenesis as well as potential therapeutic targets for HCC treatment.