结直肠癌（CRC）肿瘤细胞增殖、侵袭和转移等恶性特征是细胞失极性的外在表现。Par3是Par极性复合物（Par3-Par6-aPKC）的中心分子，在不同组织或同一组织不同病理类型肿瘤中，可发挥抑癌或促癌不同效应。Par3在CRC中表达水平？促癌？抑癌？分子机制？均不明确。我们前期工作发现，Par3在CRC中高表达，并提示患者不良预后；Par3促进CRC增殖和侵袭转移；高表达Par3的小鼠肠细胞间隙增宽，游离核糖体数目增多；Par3与翻译起始因子eIF3a相互作用，抑制后者入核。提示Par3可能通过eIF3a介导的翻译、肠干细胞分裂及肠屏障等促进CRC进程。本项目拟结合使用转基因小鼠、化学诱癌、PDX模型、类器官培养、免疫组化及分子生物学等多种实验手段，深入研究Par3促进CRC进程分子机制及eIF3a抑制剂治疗CRC的可行性，以期揭示CRC发生发展的新分子机制，探索CRC诊治的新方向。

Colorectal cancer (CRC) is ranked the third in terms of incidence and the second in terms of mortality among all cancer types in the world. CRC incidence and mortality is increasing in China. And it is now a major public health issue in the country. The main function of the intestinal tract is absorption of nutrients and packaging waste products for excretion, a process that requires proper polarized epithelia and epithelial layer of the intestinal tract. Loss of apical–basal polarity is one of the hallmarks of epithelial cancers. Polarity is established through the coordinated actions of three protein complexes: the Scrib/Lgl/Dlg complex on basolateral membranes; the Crumbs/PALS/PATJ complex on apical membranes; and the Par3/Par6/aPKC complex at the apical-basal border. ..Par3 is the central component of Par complex. It consists a conserved region in the N-terminus, three PDZ domains in the middle and an aPKC binding site followed by coiled-coil region in the C terminus. Accumulating evidence suggests that Par3 plays an important context-dependent role in mammalian tumorigenesis. For example, it has been shown that loss of Par3 promotes breast cancer metastasis by compromising cell-cell cohesion. While elevated expression of Par3 has been observed in renal clear cell carcinoma. Interestingly, a tumor type-dependent function of Par3 was found in Ras-mediated skin cancer, showing (pro)oncogenic and tumor-suppressive activity during formation of papilloma and keratoacanthomas, respectively. ..Previous studies from different groups found contradictory roles of Par3 in CRC. For instance, Yeo et al. reported that the expressions of Par3 were higher in primary CRACs as compared with that in adenomas or in metastatic CRACs. Decreased Par3 expression correlated with high proliferation rate and poor histologic differentiation. Whereas, Li et al. found that CRC tissues showed increased Par3 immunoreactivity. And Par3 overexpression was independently predictive of lower survival rate in CRC patients. On the contrary, Liu et al. reported that the expression of Par3 in CRC tissues was significantly lower than that in paired controls, and its expression negatively correlated with lymph node metastasis. The detailed molecular mechanisms of Par3 in CRC are still not clear. ..In our preliminary experiments, we found that Par3 is upregulated in CRC specimens. Over-expression of Par3 promotes cell proliferation, invasion and metastasis in vivo. In addition, we found that Par3 interacts with eIF3a, the largest unit of eukaryotic translation initiation factor 3, which is also the largest protein complex among the eukaryotic translation initiation factors. Elevated Par3 expression inhibits eIF3a nucleus translocation from cytoplasm. Moreover, over-expression of Par3 in Lgr5+ stem cells leads to dysfunction of protein translation, as indicated by increased free ribosome. These data suggested that Par3 might promotes CRC development in a translation dependent pathway...In this proposal, we plan to further investigate the role of Par3 in CRC development, including Par3 regulated eukaryotic translation, intestinal stem cell division mode and intestinal mucosal barriers and et al. We will also explore the potential application of eIF3a inhibitors in CRC treatment. We will employ a multidiscipline approach, encompassing mouse genetics, PDX model, intestinal organoid culture, immunohistochemistry, biochemistry and molecular biology and et al. to pursue our aims above. The proposed studies in this application will not only allow us to advance the knowledge of molecular mechanisms of Par3 in CRC, but may also produce new leads to treat CRC.