Dicer是RNAi途径中的关键酶，通过miRNA和siRNA调控基因表达。申请人2008年报道Dicer表达降低导致DNA损伤，随后与国内外同行一道深入研究了其分子机理：发现Dicer不仅通过同源重组和非同源末端连接参与DNA双链断裂修复，还能调节核苷酸切除修复。DNA-蛋白质交联（DPC）是一种细胞毒性较大的DNA损伤。申请人发现：炎症组织中的活性氧诱导DPC复合物生成并降低Dicer表达，Dicer表达降低导致DPC复合物增加，DPC复合物促进炎症因子表达。在此基础上，申请人提出炎症组织中Dicer表达降低可能通过增加DPC复合物加重炎症、导致炎症迁延不愈、促进炎癌转化。本项目拟研究Dicer表达降低导致DPC复合物增加的分子机理，研究DPC复合物调节炎症因子表达的分子机理，研究在慢性炎症性肝组织中清除DPC复合物是否能够减轻炎症并降低肝癌发生率，为肝癌的防治提供新思路。

Dicer is a key component of the RNA interference pathway, which is essential for the biogenesis of microRNAs and small interfering RNAs. Previously, we had reported that decreased Dicer expression causes DNA damage (Tang et al., J Cell Biol, 2008). Subsequently, our group along with others found that Dicer regulates nonhomologous end joining, homologous recombination, and nucleotide excision repair. DNA-protein crosslink (DPC), which poses a steric hindrance to transcription and replication, is one of the most deleterious and least studied forms of DNA damage. Reactive oxygen species are nonspecific inducers of DPC. Our preliminary data showed that hydrogen peroxide, a reactive oxygen species, repressed Dicer expression. Moreover, knockdown of Dicer in cultured cells increased the level of DPCs in the presence of hydrogen peroxide. The expression levels of Dicer were inversely correlated with the amount of DPCs in inflamed liver tissues. Further, DPCs regulated the expression of proinflammatory cytokines, such as interferon-β1 and interleukin-6. Based on these observations, we propose that decreased Dicer expression promotes inflammation-driven hepatocarcinogenesis by increasing the level of DPCs, which facilitates carcinogenesis by exaggerating inflammation and inducing mutation. We will test this hypothesis in the proposed study. First, we will investigate the molecular mechanisms underlying the inverse correlation between Dicer expression and DPC accumulation in inflamed liver tissues. Second, we will investigate the effect of DPCs on the activation of inflammatory pathways and the expression of inflammatory mediators and elucidate the underlying molecular mechanisms. Finally, we will address whether removing DPCs from inflamed liver tissues can alleviate inflammation and delay hepatocarcinogenesis. We expect that our study will shed light on the prevention and treatment of inflammation-associated hepatocellular carcinoma.