RNF43介导的YBX1泛素化降解抑制胰腺癌进展的机制研究

胰腺癌是最致命的疾病之一，快速进展是其预后不良的重要原因。环指蛋白43（RNF43）是一种抑癌蛋白，也是一种重要的E3泛素连接酶，我们研究发现其在胰腺癌中发生失活突变率高，且与不良预后有关。但是其导致预后不良的分子机制尚未阐明。Y盒结合蛋白1（YBX1）是一种可以调控众多细胞功能的致癌蛋白。但是RNF43与YBX1之间是否存在作用尚不清楚。我们前期的研究发现YBX1高表达促进胰腺癌的进展，预实验发现RNF43在胰腺癌中低表达，且RNF43与YBX1是存在相互作用，并且RNF43可以调控YBX1的稳定性，从而抑制胰腺癌的进展。因此申请人提出假说RNF43在胰腺癌中通过泛素化降解YBX1从而抑制胰腺癌进展。本项目拟在前期研究基础上进一步在体内体外研究中探索RNF4介导调控胰腺癌进展作用机制，为进一步阐明胰腺癌进展机制及胰腺癌的治疗新靶点提供理论基础。

Pancreatic cancer is one of the most lethal diseases. Rapid progression is an important cause of poor prognosis. Ring finger protein 43 (RNF43) is a tumor suppressor and an important E3 ubiquitin ligase. RNF43 highly inactivating mutated in pancreatic cancer and is related to poor prognosis. However, the mechanism is still not clarified. Y-box binding protein 1 (YBX1) is a multi-functional oncoprotein. We previously found that high expression of ybx1 promotes the progress of pancreatic cancer, and the preliminary experiments found that RNF43 was low expressed in pancreatic cancer. However, it is not clear whether there is a connection between RNF43 and YBX1. Mass spectrometry and Co-IP demonstrated the interaction between RNF43 and YBX1. Further, we found RNF43 regulated the stability of YBX1, thus inhibiting the progress of pancreatic cancer. Therefore, the applicant proposes that RNF43 degrades YBX1 through ubiquitination to inhibit pancreatic cancer progression. In this project, we aim to explore the mechanism of RNF4 mediated degradation of YBX1 to regulate the progression of pancreatic cancer in vivo and in vitro, and it will provide a theoretical basis for further elucidating the mechanism of pancreatic cancer progression and new targets for pancreatic cancer treatment.