微小RNA（miRNA）在肿瘤发生恶性转移中发挥重要作用，调控其生物合成是治疗肝癌等疾病的重要途径。对TRBP（转录响应元件RNA结合蛋白）介导的miRNA生物合成机制了解有限，制约了对miRNA亚型功能的认识。我们前期发现了第一个TRBP的化学小分子抑制剂-苯基噁唑类化合物3b。因此，本课题拟通过构效关系研究，提高3b靶向TRBP的特异性及活性；通过测定3b与TRBP复合物晶体结构等方法明确3b与TRBP的结合方式；通过对TRBP与pre-miRNA的结合，对Dicer和Argonaute 2功能的影响，以及对Dicer的变构调控等方面的研究，阐明TRBP调控miRNA生物合成的作用机制；研究TRBP对肝癌上皮-间质转化的影响及miRNA亚型在肝癌EMT转化中的功能和作用机制。旨在阐明TRBP调控miRNA生物合成的新机制、miRNA亚型在肝癌转移中的功能，提供肝癌诊断和治疗的新策略。

MicroRNA (miRNA) plays a key role in the occurrence of cancer metastasis, which makes regulation of miRNA biogenesis an important strategy to treat metastatic cancers including hepatocellular carcinoma (HCC). However, the mechanism of TRBP (trans-activation response element RNA-binding protein) in the regulation of miRNA biogenesis is still unclear, which limits our understanding of the function of miRNA isoforms (iso-miRNAs) with different length. Previously we identified benzyl oxazoles 3b as a first inhibitor of TRBP to inhibit the biogenesis of canonical miRNAs. In this study we will use 3b as a probe to study its structure-activity relationship to increase its activity and specificity in targeting TRBP; clarify the binding mode of 3b on TRBP by X-ray crystallographic analysis of 3b-TRBP complex; study the effects of TRBP on its binding with pre-miRNA, on the function of Dicer and Argonaute 2, and on the allosteric regulation of Dicer respectively to elucidate the mechanism of TRBP in regulating the expression of canonical miRNAs and iso-miRNAs; elucidate the function and mechanism of TRBP and iso-miRNAs on epithelial–mesenchymal transition-induced HCC metastasis. The purpose of this study is to reveal the new mechanism of TRBP in the regulation of miRNA biogenesis and iso-miRNA function in HCC metastasis, and provide new strategies for the diagnosis and treatment of HCC