ATP柠檬酸裂解酶基因沉默诱导的细胞衰老在上皮性卵巢癌中的作用及机制研究

Ovarian cancer is a common neoplasm of the female reproductive tract. Because early-stage tumors commonly show no obvious and often only unspecific signs or symptoms，most patients are suffered in advanced or has been transferred at the time of diagnosis. Therefore, it is essential to explore novel and reliable therapeutic molecular targets. We found previously that ACL was overexpressed and activated in epithelial ovarian cancer, and p-ACL expression was significantly correlated with prognosis of patients. ACL knockdown inhibited cellular proliferation and induced cell cycle arrest in A2780 and OVCAR3 cells. We also found that ACL gene silencing could induce cellular senescence. On this basis, our group will explore the pathway of ACL silencing-induced cellular senescence, and if the de novo lipid synthesis is involved in the mechanism of cellular senescence. Mouse xenograft model will be constructed to verify the mechanism of cellular senescence. At last, we will observe if ACL silencing-induced senescent A2780 cells display the canonical SASP phenomena. This project can help to provide a theoretical basis for the diagnosis and treatment of epithelial ovarian cancer.

卵巢恶性肿瘤是女性常见的生殖系统恶性肿瘤，起病隐匿，进展快，由于缺乏有效的治疗手段，患者的五年生存率较低。因此，寻找合理有效的基因治疗靶点，是提高卵巢癌生存率的关键。我们发现ACL在上皮性卵巢癌组织中表达升高且活化增强，其活性形式p-ACL表达与患者的预后相关；RNAi降调ACL表达可抑制上皮性卵巢癌A2780和OVCAR3细胞增殖，并可诱导细胞周期阻滞。我们同时发现，降调ACL表达可以诱导上皮性卵巢癌细胞发生细胞衰老。本项目将在此基础上进行以下研究：1. ACL基因沉默诱导上皮性卵巢癌发生细胞衰老的具体信号通路；2. ACL作为脂质代谢通路上的关键酶，其基因沉默引起的脂质合成改变是否直接参与细胞衰老的发生机制；3. 体内实验进行验证；4. ACL基因沉默诱导的衰老EOC细胞是否会出现典型的SASP现象，旨在为上皮性卵巢癌的诊断和治疗寻找新的有效靶标提供理论依据。