已知RNA exosome（外切体）介导RNA的降解及加工，但它与肿瘤的关系少有报道。hMTR4是细胞核内重要的RNA外切体共作用因子，但尚无hMTR4调控细胞周期的报道，也无hMTR4在调控RNA加工降解之外的作用机制研究。我们的前期研究显示，hMTR4可与p21启动子相互作用；沉默hMTR4的表达，可促进p21的转录，导致细胞周期阻滞于G1期；hMTR4水平在肝癌组织显著上调；沉默hMTR4可抑制肝癌细胞的体外和体内生长。基于此，本项目将围绕“hMTR4调控细胞周期的机制及生物学意义”这一关键科学问题，结合细胞、动物模型及人体标本开展以下研究：1、鉴定hMTR4在细胞周期调控中的作用；2、阐述hMTR4调控细胞周期的分子机制；3、揭示hMTR4对肝癌生长的影响；4、分析hMTR4在肝癌中上调的原因。研究结果将揭示hMTR4的新功能及细胞周期和肿瘤生长调控的新机制，为抗癌治疗提供新靶点。

RNA exosome is the protein complexes engaged in the degradation and processing of RNA, and its roles in cancer development remain largely unknown. hMTR4 is an important co-factor of the RNA exosome. However, there are no reports that disclose the role of hMTR4 in G1/S transition of cell cycle or characterize the function of hMTR4 other than regulating RNA degradation and processing. Our preliminary results showed that hMTR4 was associated with the promoter of p21, and silencing hMTR4 induced p21 transcription, leading to G1-arrest. Moreover, hMTR4 level was significantly upregulated in hepatocellular carcinoma (HCC) tissues, and silencing hMTR4 inhibited the proliferation of HCC cells in vitro and repressed the tumor growth in vivo. With these findings, we will focus on the key scientific issues “the mechanism and biological significance of hMTR4 in regulating cell cycle” in this project. In combination with the cell line, animal models and human specimens, we will conduct the following investigations: 1. Identify the role of hMTR4 in cell cycle regulation; 2. Clarify how hMTR4 regulates cell cycle; 3. Disclose the roles of hMTR4 in HCC growth; 4. Analyze the mechanisms underlying hMTR4 upregulation in HCC cells. The results obtained will reveal new functions of hMTR4 and regulatory mechanisms of cell cycle and tumor growth, and provide novel targets for anticancer treatment.