结肠癌细胞内Geminin/DNA-PK相互作用增强顺铂化疗损伤耐受及其干预策略的研究

DNA损伤耐受是结肠癌顺铂耐药的重要原因，寻找肿瘤细胞顺铂损伤耐受的新靶点和干预新策略对提高化疗效果至关重要。课题组前期发现Geminin可以和损伤修复蛋白DNAPK相互作用。miR571是Geminin的重要抑制分子。进一步研究发现，顺铂耐药过程中Geminin表达增高，且与miR571负相关；干涉Geminin后顺铂化疗敏感性显著增强，并抑制了NHEJ修复活性。据此我们推测，结肠癌细胞顺铂处理过程中miR571低表达解除了对Geminin的抑制，而表达增高的Geminin通过与DNA-PK相互作用增强了NHEJ修复最终导致DNA损伤耐受和耐药。本项目拟系统阐明Geminin的表达对结肠癌顺铂治疗敏感性的影响和分子机制，并在动物体内验证Geminin对顺铂耐药性的影响及其靶向干预策略作为结肠癌化疗增敏方法的可行性。本研究将阐明结肠癌顺铂耐药的新机制，并为开发逆转顺铂耐药的新策略提供依据。

DNA damage repair is an important reason of cisplatin resistance in colon cancer. It is very important to find a new target and strategy to improve the effect of chemotherapy. Our previous studies that mir-571 is an important inhibitor of Geminin. Geminin can interact with DNA-PK. Further study showed that the expression of Geminin was increased in the process of cisplatin resistance, which was negatively correlated with mir-571 expression; In addition, sensitivity of cisplatin was significantly increased after interference with Geminin,, and the repair activity of NHEJ reporter was inhibited. Therefore, we speculated that the low-level miR-571 relieved the inhibition of Geminin in the process of cisplatin treatment. Geminin confers cisplatin resistance in colon cancer via enhanced NHEJ repair. This project will first analyze the effect and molecular mechanism of Geminin on cisplatin resistance in colon cancer. Then, we will verify the effect of Geminin in animals and development of interventional strategy for sensitization. It is highly possible that we would discover a novel mechanism of cisplatin resistance in colon cancer, and thus providing a new target and new strategies for reversing cisplatin resistance.