Dicer是RNAi途径中的关键酶，申请人长期研究Dicer在消化系统慢性炎症向肿瘤恶性转化过程中的作用。发现Dicer与SIRT7（一个组蛋白去乙酰化酶）相互作用，在DNA损伤修复过程中起重要作用；SIRT7重组蛋白能够在体外抑制Dicer的酶切活性; 在大多数肝癌细胞中同时存在Dicer表达降低和SIRT7表达上升的现象。本项目拟研究SIRT7在肝癌细胞中是否能够调节miRNA的生物合成，是否通过去乙酰化调节Dicer活性来调节miRNA生物合成；是否通过调节p53表达以及DNA损伤修复来调节miRNA生物合成。阐明SIRT7在肝癌细胞中调节miRNA生物合成的机理，为肝癌的诊治提供理论基础。

Dicer, a key enzyme of the RNA interference pathway, is frequently down-regulated in human cancer tissues. The applicant has focused on the role of Dicer in inflammation-driven carcinogenesis. Recently, we found that the human Dicer protein interacts with SIRT7, an NAD+-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase, and the interaction between Dicer and SIRT7 is essential for DNA damage repair. Moreover, we found that the recombinant SIRT7 protein can repress the pre-miRNA processing activity of Dicer protein. In human primary hepatocellular carcinoma cells, Dicer down-regulation is frequently accompanied with SIRT7 up-regulation. .In this proposal, we will address whether SIRT7 can regulate miRNA biogenesis in hepatocellular carcinoma cells, and will elucidate the underlying molecular mechanisms. Firstly, we will determine whether Dicer is acetylation modified, and whether SIRT7 can deacetylate Dicer protein. Secondly, we will investigate whether the acetylation status affects the pre-miRNA processing activity of Dicer protein. Thirdly, we will address whether SIRT7 regulates miRNA biogenesis in a p53-dependent manner. Lastly, we will address whether SIRT7 regulates miRNA biogenesis via promoting DNA damage repair. Our study will shed light on the role of SIRT7 in hepatocarcinogenesis.