科罗索酸对糖尿病相关肝癌的抑制作用及其机制

Diabetes is a high risk factor of liver cancer, but its mechanism is not clear. Cat ginseng is commonly used in clinical medicine in Jiangsu and Zhejiang, corosolic acid (CA) as one of the compounds was confirmed to have both blood suger-controlling and tumor-suppression effects, revealing the function of CA will help us understand the relationship between diabetes and liver cancer. In our previous works, CA effectively inhibits the YAP protein in hepatocarcinoma, decreases the overall level of intracellular monosaccharides modified by O-GlcNAc, we also found that YAP can be modified by O-GlcNAc and O-GlcNAc, and O-GlcNAcylation is an important way to promote the level of high glucose on proliferation of hepatoma cells. Therefore, we put forward the hypothesis that YAP and O-GlcNAc form a "vicious circle", promoting cancer growth in high glucose environment, but CA can effectively block the cycle. This project will provide a theoretical basis for the relationship between diabetes and liver cancer.

糖尿病是肝癌的高危因素，但其机制不明。猫人参是江浙地区临床常用中药，科罗索酸（Corosolic Acid, CA）作为其中一种化合物，被证实同时具有降血糖与抗肿瘤两方面作用，因此，揭示CA功能有助于我们理解糖尿病与肝癌之间的关系。在前期研究中，课题组证实CA能有效抑制肝癌细胞中重要癌蛋白YAP表达，降低胞内单糖O-GlcNAc修饰的整体水平；同时我们还发现，YAP可以被O-GlcNAc修饰而增加稳定性，而单糖O-GlcNAc修饰又是高糖水平促进肝癌细胞增殖的重要途径。因此我们提出假设，在高糖环境中YAP与O-GlcNAc修饰互相促进形成促癌生长的“恶性循环”，CA可有效阻断这一循环。本项目将对此进行验证，为明确糖尿病与肝癌的关系提供理论基础。

糖尿病是肝癌的重要危险因素，但其发病机制尚不清楚。科罗索酸(Corosolic acid，CA)已被证实具有降血糖和抗肿瘤的双重作用，因此揭示CA的功能有助于我们了解糖尿病与肝癌的关系。在以往的研究中，我们证实CA能有效抑制肝癌细胞中重要的癌蛋白YAP的表达，抑制肝癌细胞的增殖。此外，我们还发现O-GlcNAcylation在肝癌的发生发展中起着不可或缺的作用。然而，CA是否能抑制高糖作用下肝癌细胞中O-GlcNAcylation的作用尚不清楚。本研究通过CA抑制高糖作用下肝癌细胞内的O-GlcNAcylation水平探讨其抗肿瘤作用及其机制。研究结果表明，高糖能促进肝癌细胞的增殖，而CA在高糖作用下能抑制肝癌细胞的生长，在小鼠移植瘤模型中能抑制肿瘤的生长。CA可抑制高糖下HBP通路的激活，降低YAP和OGT的表达。更重要的是，我们发现CA可以通过抑制CDK19的活性来降低YAP和O-GlcNAcylation的表达。CDK19的过表达可部分逆转CA引起的YAP和O-GlcNAcylation的降低。这是首次有证据表明CA可通过失活CDK19/YAP/O-GlcNAcylation途径降低高糖细胞的增殖能力，进而抑制肿瘤生长，提示CA可能是抗糖尿病相关肝癌的候选药物。