GGCT重构线粒体稳态促进高级别浆液性卵巢癌铂类耐药的作用和机制

高级别浆液性卵巢癌（HGSC）死亡率居妇科恶性肿瘤之首，铂类化疗耐药是治疗的主要障碍，机制不清。肿瘤细胞维持线粒体稳态的适应性改变在耐药诱导中起重要作用。GGCT是项目组自主筛选获得的促癌蛋白，参与GSH代谢，预实验提示其与HGSC铂类耐药相关。GGCT敲低肿瘤细胞GSH含量及GSH/GSSG比率下降，ROS增加，对顺铂敏感性增强；GGCT过表达致肿瘤细胞线粒体自噬增强，同时线粒体自噬受体BNIP3表达升高。我们推测GGCT调节细胞内氧化还原平衡，减少线粒体氧化损伤并促进BNIP3介导的线粒体自噬而重塑线粒体稳态，促使HGSC铂类耐药。本项目拟首先评价GGCT作为HGSC铂敏感性分子标志物的价值，然后利用基因敲除和原位PDX模型等手段进一步明确GGCT在HGSC铂类耐药中的作用和机制，并探索基于GGCT抑制的铂类化疗增效和耐药逆转的新思路，为铂类耐药HGSC治疗新靶点的确立提供理论依据。

High grade serous ovarian cancer (HGSC) is the most lethal gynecological malignancy. Platinum chemoresistance is the main obstacle to treatment, and the mechanism is unclear. Adaptation of tumor cells to maintaining mitochondrial homeostasis plays an important role in the induction of chemoresistance. We originally identified GGCT as a cancer promoter through a proteomic study, which participates in GSH metabolism. Our preliminary study indicated that GGCT was associated with primary and secondary platinum resistance in HGSC. GGCT-knockdown tumor cells showed decreased GSH content and GSH/GSSG ratio , as well as increased ROS and sensitivity to cisplatin. Overexpression of GGCT resulted in enhancive mitophagy in tumor cells, and increased expression of BNIP3. We speculate that GGCT regulates intracellular redox balance, reduces mitochondrial oxidative damage and promotes BNIP3-mediated mitophagy to reshape mitochondrial homeostasis and promote platinum chemoresistance in HGSC. The current project intends to first evaluate the value of GGCT as a molecular marker of HGSC patient's platinum sensitivity status, and then use gene knockout and in situ PDX models to further clarify the role and mechanism of GGCT in HGSC platinum resistance in vivo and in vitro, as well as exploring new strategies based on GGCT inhibition to overcome platinum resistance in HGSC. Further, theoretical basis for the establishment of new targets for platinum-resistant HGSC treatment may be provided.