AGEs通过PLK1-CEP20诱发肝细胞中心体扩增进而诱发肿瘤发生的分子机制研究

糖尿病与癌症二者之间存在的高风险相关性已被流行病学证实，但糖尿病诱发肿瘤的机理仍然不明。本项目前期研究结果表明糖尿病病理因素糖基化终末产物（AGEs）可诱发肝细胞中心体扩增，而中心体扩增是导致基因组不稳定性的重要因素，这是细胞癌变的前提。因此探究AGEs诱发中心体扩增的分子机理是揭示糖尿病诱发癌症的关键。转录组分析表明AGEs显著上调肝细胞PLK1与CEP20的表达，siRNA干扰证实PLK1和CEP20是AEGs诱发肝细胞中心体扩增的关键蛋白。中心体扩增的原因最终均可归结为复制循环的紊乱和中心体组装的异常。因此本课题将聚焦PLK1-CEP20调控中心体复制周期及组装的机理研究，揭示PLK1-CEP20表达或功能异常导致中心体扩增的分子机理。并验证PLK1-CEP20表达或功能异常导致的中心体扩增是否是AGEs诱发肝细胞发生恶性转变的主要因素。这将为探究糖尿病诱发肿瘤提供理论基础。

The high-risk correlation between diabetes and cancer has been confirmed by epidemiology, but the mechanism of diabetes-induced tumors is still unknown. Preliminary research results of this project indicate that AGEs, a pathological factor of diabetes, can induce hepatocyte centrosome amplification which could lead to genome instability, a prerequisite for cell carcinogenesis. Therefore, exploring the molecular mechanism of centrosome amplification induced by AGEs is the key to revealing that diabetes induces cancer. Transcriptome analysis showed that AGEs significantly up-regulated the expression of PLK1 and CEP20 in hepatocytes, and siRNA interference confirmed that PLK1 and CEP20 are key proteins for AEGs to induce centrosome amplification. The cause of centrosome amplification can ultimately be attributed to the disorder of the replication cycle and the abnormal assembly. Therefore, this research will focus to reveal the molecular mechanism of how PLK1-CEP20 regulating the centeosome duplication cycle and assembly, and verify centrosome amplification caused by the disorder expression of PLK1-CEP20 is the main reason for hepatoma genesis induced by AGEs. This will provide a theoretical basis for exploring diabetes-induced tumors.