基因可变剪切的异常是肝癌发生、发展的重要因素，但其调控机制尚不清楚。我们发现：剪切体重要组分PRP19在人原发性肝癌组织和化学诱导肝癌小鼠肝组织中，表达均显著升高，并与肝癌的预后不良相关；进而构建了肝脏条件性敲除PRP19基因小鼠，该小鼠在诱癌模型中肝癌的严重程度较轻。机制研究示PRP19与表观遗传调控因子EZH2 pre-mRNA直接结合，使5号外显子产生可变5’端剪切接入，改变长短剪切异构体比例；EZH2长异构体的表达可促进肿瘤生物学行为，与肝癌预后不良相关。提示PRP19可能通过调控EZH2的可变剪切，产生异常剪切体，继而影响EZH2下游重要癌/抑癌基因的表观遗传学变化，促进肝癌的发生、发展。本项目拟利用条件敲除基因小鼠、原代肝细胞及肝癌细胞、临床肝癌资料，在动物水平、细胞水平和人体水平，探讨PRP19通过调控可变剪切对肝癌发生发展的影响，以期为肝癌治疗提供新的分子靶点和预后指标。

Abnormal alternative splicing of genes play vital roles in tumorigenesis and progression of hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remains unclear. We found that pre-mRNA processing factor 19 (PRP19), an important member of the spliceosome, was significantly upregulated in clinical HCC tumor tissues and livers of chemical-induced HCC mice. The increased expression of PRP19 was correlated with poor prognosis of HCC. Then we constructed liver-specific PRP19 conditional knockout mice, of which the severity of hepatoma was milder in the chemo-inducing model. Mechanism study showed that PRP19 could combine with pre-mRNA of epigenetic regulation factor the enhancer of zeste homolog 2 (EZH2). Loss of PRP19 could cause the alternative splice of pre-mRNA exon5 in EZH2, resulting in alteration of ratio of EZH2-exon5 long isform (EZH2-E5L) to short isform (EZH2-E5S). The expression of EZH2-E5L transcripts promoted tumor behaviors in hepatoma cells. Moreover, the increased expression of EZH2-E5L transcripts was related to poor HCC prognosis. In all, PRP19 may regulate HCC carcinogenesis and development through its alternative splicing of EZH2. PRP19 may regulate alternative splicing of EZH2 and produce abnormal isoforms, by which interfering the epigenetic effect on downstream genes of EZH2, thus promoting HCC progression. We will use liver-specific gene conditional knockout mice, primary hepatocytes and liver cancer cells, along with clinical liver cancer data to explore the role of PRP19 in the carcinogenesis and development of HCC via regulating alternative splicing at animal level, cell level and human level. Our study will provide a new molecular target and a prognostic marker for HCC treatment.