LncRNA L12–PTPRZ1通路在葡萄膜黑色素瘤靶向治疗中的作用机理研究

葡萄膜黑色素瘤（Uveal melanoma, UM）是我国成人发生率最高的眼内恶性肿瘤，治疗难，预后差，死亡率高。近来针对UM表观遗传学改变的治疗策略，因有望达到个体化靶向治疗的目的，逐渐成为研究热点。课题组前期研究发现核内长非编码RNA L12在UM发生中起促癌作用，并明确PTPRZ1是L12介导的下游关键癌基因，提示我们可通过靶向L12-PTPRZ1通路发挥对UM调控作用。因此，本项目提出以L12-PTPRZ1通路为突破口，开展UM治疗新靶点新方法的研究。利用ChIP等技术辨别L12介导下PTPRZ1遗传修饰状态及关键调控因子，通过CRISPR技术、小分子抑制剂、中和抗体等研究L12-关键调控因子-PTPRZ1通路在UM靶向治疗中的作用及机制。本项目的开展将为从lncRNA-靶基因调控角度探寻UM表观治疗提供依据，探寻杀伤UM的潜在靶点，推进UM靶向治疗的研究。

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, resulting in poor outcome with visual loss and high death rate. Given the potentials for patients receiving individualized targeted therapy, epigenetic treatment of UM has been the hot field of recent researches. We previously revealed that L12 lncRNA promoted the progression of UM through its target gene PTPRZ1, thus, we hypothesized that L12-PTPRZ1 pathway played a critical role in the tumorigenesis of UM through some key epigenetic modifying factors, and targeting this pathway can potentially uncover a new therapeutic strategy. To test this hypothesis, we intend to use ChIP to find the key epigenetic modification factor, and use CRISPR, small-molecular inhibitors, and antibody to illustrate the potentials of this lncRNA-gene pathway in the treatment of UM. In conclusion, we will increase the understanding of the role of lncRNA-gene pathway in the treatment of UM, contribute to the enrichment of epigenetic therapy targets, and promote the development of targeted therapy.