CRL4促进卵巢癌顺铂耐药的分子机制研究

Cisplatin resistance is a huge challenge for the cure of recurrent ovarian cancer. Our preliminary data suggested that CRL4 played a crucial role in the cisplatin resistance of ovarian cancer and may function through regulating its downstream targets including BIRC3 and COX7C. Based on these results, we propose to further study the mechanism through which CRL4 promotes ovarian cancer cisplatin resistance, using techniques including Co-IP, ChIP and IF. First, we will complete the detailed mechanism of how CRL4 regulates BIRC3; Next, we will mainly focus on studying the mechanism of how CRL4 promotes ovarian cancer cisplatin resistance by manipulating COX7C expression; Last, we will also briefly study the role of the other CRL4 downstream targets in CRL4 promotion of ovarian cancer cisplatin resistance. We aim to find novel targets that are specific for resistant tumors, thus to break the bottleneck of cisplatin resistance in clinical treatment and provide new thoughts for more efficient chemotherapy.

顺铂耐药一直是临床治疗卵巢癌的瓶颈。我们前期的研究结果显示CRL4在卵巢癌细胞顺铂耐药中发挥重要功能，且该功能可能通过调节下游靶基因BIRC3和COX7C的表达实现。本项目拟在该基础上，通过Co-IP、ChIP、IF等手段，深入探索并完善CRL4调控卵巢癌顺铂耐药性的具体分子机制。首先，我们将进一步完善CRL4调节BIRC3表达的分子机制；其次，我们将主要探索CRL4通过调节COX7C的表达水平促进卵巢癌顺铂耐药的分子作用机制；最后，我们将简要分析其它与化疗耐药相关的CRL4下游靶基因在CRL4调控卵巢癌顺铂耐药性中的作用。本项目旨在寻找针对耐药肿瘤治疗的新靶点，以突破临床治疗瓶颈，为更有效的化疗提供新思路。

化学耐药性长期以来一直是卵巢癌预后的瓶颈。已经表明，线粒体在细胞对化疗的反应中起着至关重要的作用，并且失调的线粒体动力学与卵巢癌等疾病错综复杂地相关，但潜在的机制仍然不清楚。在这里，我们展示了一种新机制，其中CRL4CUL4A/DDB1通过调节线粒体动力学和线粒体自噬来操纵卵巢癌细胞的化疗耐药性。CRL4CUL4A/DDB1 耗尽通过上调 AMPKαThr172 和 MFFSer172/Ser146 磷酸化来增强线粒体裂变，进而将 DRP1 募集到线粒体。CRL4CUL4A/DDB1 缺失通过Parkin-PINK1途径刺激线粒体自噬，降解功能失调和破碎的线粒体。重要的是，CRL4CUL4A/DDB1的缺失抑制了卵巢癌细胞增殖，而抑制自噬部分逆转了这种破坏。我们的研究结果为CRL4 E3泛素连接酶复合物在调节线粒体裂变，线粒体自噬和卵巢癌化疗耐药的多方面功能提供了新的见解。破坏CRL4CUL4A/DDB1和线粒体自噬有望成为克服卵巢癌化疗耐药性的有效治疗策略。