MIER3通过MRGBP介导乙酰化修饰途径抑制结直肠癌侵袭转移的分子机制

课题组前期研究发现MIER3在结直肠癌中表达下调，并与结直肠癌的侵袭、转移及临床预后相关，其过表达可抑制结直肠癌细胞的增殖、迁移及侵袭能力，并与结肠癌EMT密切相关。进一步，利用 CoIP结合质谱分析发现MIER3能与乙酰转移酶Tip/NuA4亚基MRGBP直接结合，通过抑制其表达影响乙酰化修饰作用。因此我们推测，MIER3可能通过MRGBP介导乙酰化修饰途径，调控某些关键基因的表达，进而调控结直肠癌的侵袭和转移。本项目拟利用RNAi、过表达等在体内、体外进一步明确MIER3在结直肠癌侵袭转移中的作用；CoIP、GST pull-down等验证确定MIER3和MRGBP的相互作用方式及结合域，在此基础上应用基因芯片分析MIER3与MRGBP 所共同调控的关键信号分子，明确它们内在功能联系，从而阐明一条完整的MIER3抑制结直肠癌侵袭转移的分子机制，为基于MIER3通路靶向治疗奠定理论基础。

Metastatic spreading is the main cause of cancer-related deaths. We previously demonstrated that MIER3 expression was significantly decreased in colorectal carcinoma (CRC), which was correlated with invasion, metastasis and clinical prognosis in patients with CRC. Up-regulation of MIER3 significantly inhibited proliferation, migration and invasiveness of CRC cells in vitro. Co-immunoprecipitation (CoIP) assays combined with mass spectrography revealed that MRGBP is a potentially direct interaction protein of MIER3 in CRC. Furthermore, it was demonstrated that the overexpression of MIER3 could suppress the expression of MRGBP and could change the acetylation modification for histone. Based on these findings, we hypothesize that MIER3 could inhibit MRGBP expression, and then induce some key genes by modifying acetylation state of histones, which mediating cell proliferation and metastasis in CRC. In this study, we will evaluate the function of MIER3 in CRC in vivo and in vitro by gain and loss of function model. Furthermore, we will explore the action way and motifs between MIER3 and MRGBP using CoIP assays, GST pull-down, and so on. Furthermore, the signaling molecules regulated by MIER3 and MRGBP are analyzed though gene expression microarrays，and establish a functional link among key molecules, MIER3 and MRGBP. The research will uncover the pathway of MIER3 effects on CRC, and will provide basic knowledge for future therapy of the MIER3 signaling pathway.