MORN3促进p53蛋白质泛素化降解并影响结直肠癌发生的机制研究

Colorectal cancer occurrence is increasing during past years, and its development is related to the inactivation of p53. Approximately half colorectal cancer cases were found without TP53 mutations, but the mechanisms for its inactivation remain unclear. In our previous studies, we found Morn3 is upregulated and amplified in CRC with oncogenic functions. Further study suggested that Morn3 promotes ubiquitin-dependent degradation of p53 protein, and both proteins physically interacts with each other. However, the detailed mechanisms for Morn3's regulation on p53 is still unclear. In the present study, we aim to clarify the regulation of Morn3 on p53 by identifying the detailed binding regions between Morn3 and p53. We also aim to identify the E3 ubiquitin ligase that modifies p53 with the aid of Morn3. This study will clarify the relationship beteween Morn3 expression and the clinicopathological features of CRC patients, to provide new insights into the CRC oncogenesis and help the development of more effective anti-cancer therapies.

结直肠癌在我国的发病率逐年升高，其发生与抑癌因子p53的失活密切相关。约有一半结直肠癌中TP53基因未发生突变，而其失去功能的机制尚未完全阐明。我们前期研究发现Morn3这种功能未知的基因在结直肠癌中拷贝数扩增并且表达上调，具有促癌功能。进一步研究提示Morn3促进p53的泛素化修饰和蛋白酶体途径的降解，且Morn3与p53蛋白质发生直接的相互作用。然而，Morn3调控p53的具体分子机制还有待于研究。因此本项目拟通过各种体内外研究揭示Morn3与p53在结直肠癌中的具体作用机制，明确Morn3与p53的结合区域，确定Morn3招募的泛素化连接酶，研究Morn3对p53下游通路的影响，并通过分析Morn3与肿瘤病人临床病理的关系进一步探讨Morn3作为分子标记物及干预因子的价值，为发展更为有效的分子靶向治疗提供理论依据。

本课题按照计划执完整地行了研究任务，探讨MORN repeat containing 3 (Penguin)通过调节p53的翻译后修饰促进结直肠癌发生发展的功能。在具体机制方面，发现penguin结合p53的C末端，并且促进该区域多聚泛素化的修饰，这种调节作用在结直肠癌等肿瘤中p53的异常失活发挥重要作用。此外，还在相关机制的基础上开发了靶向干预的多肽，用于在肿瘤细胞中重新激活p53并抑制肿瘤发生发展。在p53翻译后修饰研究结果的启发下，课题组还进一步揭示了其他重要癌相关蛋白的翻译后修饰机制（包括PD-L1, PD-1等），这些研究加深了对于肿瘤中关键蛋白质失调控的系统性全局性认知，并对肿瘤的干预新靶标发现提供了新的理论依据。综上所述，原定研究计划已经执行完成。