Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong, 250012, PR China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong, 250012, PR China.
Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden.
Cancer Lett. 2024 Oct 10;602:217192. doi: 10.1016/j.canlet.2024.217192. Epub 2024 Aug 22.
PARPi is currently the most important breakthrough in the treatment of ovarian cancer in decades, and it has been integrated into the initial maintenance therapy for ovarian cancer. However, the mechanism leading to PARPi resistance remains unelucidated. Our study aims to screen novel targets to better predict and reverse resistance to PARPi and explore the potential mechanism. Here, we conducted a comparative analysis of differentially expressed genes between platinum-sensitive and platinum-resistant groups within the TCGA ovarian cancer cohort. The analysis indicated that lncRNA PART1 was significantly highly expressed in platinum-sensitive patients compared to platinum-resistant individuals in TCGA-OV cohort and further validated in the GEO dataset and Qilu hospital cohort. Moreover, the upregulation of PART1 was positively correlated with a favorable prognosis in ovarian cancer. Furthermore, in vitro and in vivo experiments showed that inhibition of PART1 conferred resistance to both cisplatin and PARP inhibitor and promoted cellular senescence. Senescent cells are more resistant to chemotherapeutics. RNA antisense purification and RNA immunoprecipitation assays revealed an interaction between PART1 and PHB2, a crucial mitophagy receptor. Knockdown of PART1 could promote the degradation of PHB2, impairing mitophagy and leading to cellular senescence. Rescue assays indicated that overexpression of PHB2 remarkably diminished the resistance to PARPi and cellular senescence caused by PART1 knockdown. PDX models were utilized to further confirm the findings. Altogether, our study demonstrated that lncRNA PART1 has the potential to serve as a novel promising target to reverse resistance to PARPi and improve prognosis in ovarian cancer.
PARPi 是几十年来卵巢癌治疗的最重大突破，已被纳入卵巢癌的初始维持治疗中。然而，导致 PARPi 耐药的机制仍不清楚。本研究旨在筛选新的靶点，以更好地预测和逆转 PARPi 耐药性，并探讨潜在的机制。在这里，我们对 TCGA 卵巢癌队列中铂类敏感和铂类耐药组之间差异表达的基因进行了比较分析。分析表明，lncRNA PART1 在 TCGA-OV 队列中铂类敏感患者中明显高表达，在 GEO 数据集和齐鲁医院队列中得到进一步验证。此外，PART1 的上调与卵巢癌的良好预后呈正相关。此外，体外和体内实验表明，PART1 的抑制赋予了顺铂和 PARP 抑制剂的耐药性，并促进了细胞衰老。衰老细胞对化疗药物更具耐药性。RNA 反义纯化和 RNA 免疫沉淀实验揭示了 PART1 与 PHB2 之间的相互作用，PHB2 是一种重要的线粒体自噬受体。PART1 的敲低可以促进 PHB2 的降解，损害线粒体自噬并导致细胞衰老。挽救实验表明，PHB2 的过表达显著减轻了由 PART1 敲低引起的 PARPi 耐药性和细胞衰老。PDX 模型被用于进一步证实这些发现。总之，本研究表明，lncRNA PART1 有潜力成为一种新的有前途的靶点，以逆转 PARPi 耐药性并改善卵巢癌的预后。
