Blockade of the lncRNA-PART1-PHB2 axis confers resistance to PARP inhibitor and promotes cellular senescence in ovarian cancer

IF 9.1 1区 医学 Q1 ONCOLOGY Cancer letters Pub Date : 2024-08-22 DOI:10.1016/j.canlet.2024.217192
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Abstract

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.

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阻断lncRNA-PART1-PHB2轴可使卵巢癌患者对PARP抑制剂产生抗药性并促进细胞衰老。
PARPi 是目前卵巢癌治疗领域数十年来最重要的突破,已被纳入卵巢癌的初始维持治疗中。然而,导致PARPi耐药的机制仍未阐明。我们的研究旨在筛选新型靶点,以更好地预测和逆转 PARPi 的耐药性,并探索其潜在机制。在此,我们对 TCGA 卵巢癌队列中铂敏感组和铂耐药组之间的差异表达基因进行了比较分析。分析表明,在TCGA-OV队列中,与铂类耐药个体相比,lncRNA PART1在铂类敏感患者中明显高表达,并在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,抑制PART1会使细胞对顺铂和PARP抑制剂产生耐药性,并促进细胞衰老。衰老细胞对化疗药物的抵抗力更强。RNA反义纯化和RNA免疫沉淀实验揭示了PART1与PHB2(一种重要的有丝分裂受体)之间的相互作用。敲除PART1可促进PHB2的降解,从而损害有丝分裂并导致细胞衰老。拯救实验表明,过表达 PHB2 能显著降低 PART1 敲除引起的 PARPi 抗性和细胞衰老。我们利用 PDX 模型进一步证实了这些发现。总之,我们的研究表明,lncRNA PART1有望成为逆转PARPi耐药性和改善卵巢癌预后的新靶点。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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