MOV10参与肿瘤DNA损伤耐受的机制及功能研究

Radiotherapy and chemotherapy are the most commonly used strategies in cancer therapy, mainly by generating DNA damage and thus killing cancer cells. However, some cancer cells can well tolerate DNA damage, which causes major obstacles for patients receiving clinical radiotherapy or chemotherapy. Therefore, complementing the understanding of the mechanism of DNA damage tolerance in cancer cells will help to figure out new targets in cancer therapy, and rationally develop personalized therapeutic regimen for better anti-tumor efficacy. . Our previous study found that the expression level of MOV10 is negatively correlated with the survival rate of patients and the protein may be involved in the DNA damage response and repair process. Our project will focus on three aspects: (1) the role of MOV10 in DNA damage response and repair in cancer cells; (2) the molecular mechanism of MOV10 in DNA damage tolerance; (3) the function of MOV10 in tumorigenesis. Through in-depth research of this project, we will finally demonstrate the new function of MOV10, and further reveal the mechanism of both tumorigenesis and DNA damage tolerance. Furthermore, our work will provide a new target for radiotherapy, chemotherapy and drug development.

放、化疗是抗肿瘤治疗中最常用的手段，主要通过在肿瘤细胞中造成DNA损伤杀灭肿瘤。然而，部分肿瘤具有较强的DNA损伤耐受能力，放、化疗难以直接杀灭肿瘤，这对患者的临床治疗造成重大阻碍。因此，补全对肿瘤DNA损伤耐受机制的认知，将有助于寻找新的抗肿瘤靶点，更合理地开发制定个性化的肿瘤治疗方案，提高抗肿瘤效应。. 我们的前期研究发现，MOV10的表达水平与肿瘤患者生存率成负相关性，且该蛋白可能参与DNA损伤应答和修复过程。因此，本项目将围绕三方面具体开展研究：（1）MOV10在肿瘤细胞DNA损伤应答与修复中的功能；（2）MOV10参与肿瘤DNA损伤耐受的分子机制；（3）MOV10在肿瘤发生发展中的新功能。通过本项目的深入研究，我们将揭示MOV10的新功能，进一步阐述肿瘤的发生发展机制与DNA损伤耐受的分子机制。同时，该研究也将为肿瘤的放、化疗研究和药物开发提供新的潜在靶点。

随社会老龄化加剧，衰老相关性疾病的发生率和致死率逐年攀升，给社会和国民健康带来沉重负担。DNA损伤是压力诱导衰老的关键诱因之一，补全对DNA损伤应答和修复机制的认知对延缓衰老，防治衰老相关性疾病具有重要意义。本项目研究发现，RNA解旋酶MOV10响应DNA损伤应答，促进DNA损伤修复过程，其功能发挥依赖于解旋酶活性。MOV10缺失将加速细胞衰老，加剧肺纤维化进程。进一步，以新冠病毒为模型进行研究。新冠病毒感染加剧肺部衰老，病毒感染所致重症、危重症也多发于老年人中。如何阻断病毒复制以及病毒感染引发的炎症因子风暴对于缓解老龄化社会负担同样具有重要作用。本研究发现，MOV10下游分子miRNA let-7可靶向抑制SARS-CoV-2中S和M蛋白表达，抑制多种炎症因子水平。利用小分子化合物C1632可整体上调let-7水平，进而抑制新冠病毒复制及病毒感染引发的炎症因子风暴，该小分子化合物有望成为新冠病毒治疗的候选药物。.本项目研究为衰老和衰老相关性疾病的发生发展机制进行了必要补充，对延缓衰老相关性疾病进程，减轻老龄化社会压力具有重要价值。