O-GlcNAc修饰YAP介导PAICS转录本的m6A甲基化促进肝母细胞瘤增殖及检验标志物开发研究

肝母细胞瘤（Hepatoblastoma，HB）是一种高恶性的肝肿瘤，好发于婴幼儿，缺乏理想的诊疗手段，严重危害患儿健康。申请人长期从事肝脏肿瘤研究，在Hippo/YAP通路以及蛋白O-GlcNAc糖基化修饰方面形成一系列重要研究成果。有趣的是，在前期研究中我们发现HB组织中同时存在蛋白O-GlcNAc糖基化修饰与RNA的m6A修饰异常活跃现象，而作为HB最重要的驱动蛋白YAP处于两种重要致癌机制的交叉点：YAP被O-GlcNAc修饰后能有效招募m6A甲基转移酶修饰靶基因转录本，其中PAICS转录本被修饰后稳定性增加表达水平增高，导致其合成的代谢产物SAICAR增加，SAICAR又进一步促进HB增殖，极可能是HB形成的重要途径。LC-MS/MS检测到HB患儿血清中SAICAR水平明显升高。本项目拟进一步研究其机制，并弥补特异性HB检测标志物的空白，具有重要研究与转化价值。

Hepatoblastoma (HB) is a kind of highly malignant liver tumors, which often occurs in infants and children. It lacks ideal diagnostic and therapeutic methods and seriously endangers the health of children. The applicant has been engaged in liver cancer research for a long time, and has formed a series of important research results in Hippo/YAP pathway and the relationship between glycosylation modification of protein O-GlcNAc and liver cancer. Interestingly, in previous studies, we found that both O-GlcNAc glycosylation and m6A modification of RNA were abnormally active in HB tissues. YAP, the most important driving protein of HB, was at the intersection of two important carcinogenic mechanisms: YAP modified by O-GlcNAc could effectively recruit m6A methyltransferase modified target gene transcripts, in which PAICS transcripts became more stable after modification. Increased expression of SAICAR leads to increased synthesis of metabolite SAICAR, further promotes the proliferation of HB, which may be an important pathway for the formation of HB. Using LC-MS/MS, we detected a significant increase in serum SAICAR levels in children with HB. This project intends to further study its mechanism and to develop a novel biomarker for HB, and has important research and translation value.