YAP介导R-loop形成增强SETBP1基因表达促进葡萄膜黑色素瘤转移

葡萄膜黑色素瘤（Uveal melanoma, UM）是成人最常见的眼内原生恶性肿瘤。UM转移率高，由于转移后缺乏有效的治疗手段导致高致死率，抑制UM转移是临床额待解决的难题。UM驱动基因GNAQ/11突变-FAK/LATS-YAP通路是调控转移的重要机制之一，然而YAP下游分子机制尚不明确。申请人在前期预实验中发现YAP在UM中介导RNA-DNA 3D结构R-loop形成，从而增加 SETBP1表达，最终促进UM转移。本项目拟以此为基础，综合运用RNA-seq，Chip-seq，IP-MASS测序技术，结合Crispr敲除体系、生化分子方法和小鼠眼肿瘤转移模型，深入研究SETBP1调控UM转移的分子机制，进一步发现和验证SETBP1及其复合物组分相关抑制剂，并与现有临床靶向药物联合治疗，为UM转移的靶向治疗提供新的方案。

Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults. The metastasis rate of UM is high, and the lack of effective treatment after metastasis leads to high mortality. Inhibition of UM metastasis remains a difficulty in clinical therapy. The UM driver gene GNAQ /11 mutation-FAK /LATS-YAP pathway is one of the important mechanisms for regulating metastasis, however, the downstream molecular mechanism of YAP remains unclear. The applicant found in the previous experiment that YAP mediates the formation of RNA-DNA 3D structure R-loop, which increases SETBP1 expression and finally promotes UM metastasis. Based on this, this project intends to use RNA-Seq, Chip-Seq and IP-Mass sequencing technologies comprehensively, combined with Crispr knockout system, biochemical molecular methods, and mouse eye tumor metastasis model, to deeply study the molecular mechanism of SETBP1 regulating UM metastasis, and reveal the target genes of SETBP1 and its epigenetic modification complex components. Based on these mechanism studies, the applicant will furtherly develop and verify the relevant inhibitors SETBP1 and its complex component, and combine them with existing clinical targeted drugs to provide a new scheme for targeted therapy of UM metastasis.