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Ascites exosomal lncRNA PLADE enhances platinum sensitivity by inducing R-loops in ovarian cancer

Oncogene volume 43, pages 714–728 (2024)Cite this article

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Abstract

Cisplatin resistance is a major cause of therapeutic failure in patients with high-grade serous ovarian cancer (HGSOC). Long noncoding RNAs (lncRNAs) have emerged as key regulators of human cancers; however, their modes of action in HGSOC remain largely unknown. Here, we provide evidence to demonstrate that lncRNA Platinum sensitivity-related LncRNA from Ascites-Derived Exosomes (PLADE) transmitted by ascites exosomes enhance platinum sensitivity in HGSOC. PLADE exhibited significantly decreased expression in ascites exosomes and tumor tissues, as well as in the corresponding metastatic tumors from patients with HGSOC cisplatin-resistance. Moreover, HGSOC patients with higher PLADE expression levels exhibited longer progression-free survival. Gain- and loss-of-function studies have revealed that PLADE promotes cisplatin sensitivity by suppressing cell proliferation, migration and invasion, and enhancing apoptosis in vitro and in vivo. Furthermore, the functions of PLADE in increasing cisplatin sensitivity were proven to be transferred by exosomes to the cultured recipient cells and to the adjacent tumor tissues in mouse models. Mechanistically, PLADE binds to and downregulates heterogeneous nuclear ribonucleoprotein D (HNRNPD) by VHL-mediated ubiquitination, thus inducing an increased amount of RNA: DNA hybrids (R-loop) and DNA damage, consequently promoting cisplatin sensitivity in HGSOC. Collectively, these results shed light on the understanding of the vital roles of long noncoding RNAs in cancers.

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Fig. 1: PLADE was downregulated in ascites exosomes and tumors from cisplatin-resistant HGSOC patients.
Fig. 2: Overexpression of PLADE promoted cisplatin sensitivity in vitro and in vivo.
Fig. 3: Knockdown of PLADE reduced cisplatin response in HGSOC cells.
Fig. 4: PLADE overexpression mediated by exosomes promoted cisplatin sensitivity in vitro and in vivo.
Fig. 5: PLADE interacts with HNRNPD in HGSOC cells.
Fig. 6: PLADE promotes the VHL-mediated ubiquitination of HNRNPD.
Fig. 7: PLADE downregulation of HNRNPD induced R-loop accumulation and DNA damage.
Fig. 8: A proposed working model of PLADE in enhancing platinumsensitivity of HGSOC.

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Data availability

All original data generated from Next Generation Sequencing (NGS) in this study have been deposited in the Gene Expression Omnibus (GEO) database under the accession number GSE247337. All study data and materials are included in the article and/or supporting information.

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Funding

Funding

This study is supported by the National Key Research and Development Program (2019YFA0802600 and 2022YFC2403400), the National Natural Science Foundation of China (82172773, 32270590, 31930019), the Anhui Provincial Key Research and Development Program (2022e07020013), Natural Science Foundation of Anhui Province (2208085QH252), the 2020 USTC Affiliated Hospital Introduction Project to Medical Leading Technology (2020LXJS-05), Beijing Science & Technology Innovation Fund (KC2021-JX-0186-143), Natural Science Research Project of Colleges and Universities in Anhui Province (2022AH051255).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China

    Hanyuan Liu, Sisi Deng, Yi Liu, Lili Qian, Yingying Wang, Tianjiao Zhang & Ying Zhou

  2. Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China

    Xuelin Yao

  3. Department of Clinical Laboratory, The First Affiliated Hospital of USTC, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230027, China

    Ge Shan

  4. Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China

    Liang Chen

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Contributions

GS, LC and YZ conceived, designed, and supervised all the experiments. HYL, and SSD conducted the experiments and most of the analysis. XLY, YL, LLQ, and YYW analyzed the remaining analysis. TJZ collected clinical samples. HYL, LC wrote the original draft of the manuscript. HYL, GS, LC, and YZ revised the manuscript and provided critical discussions. GS, LC and YZ provided the fundings for this study. All authors read, discussed and approved the final version of the manuscript.

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Correspondence to Ge Shan, Liang Chen or Ying Zhou.

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YZ, LC and GS have an ownership interest in a patent related to this research.

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Liu, H., Deng, S., Yao, X. et al. Ascites exosomal lncRNA PLADE enhances platinum sensitivity by inducing R-loops in ovarian cancer. Oncogene 43, 714–728 (2024). https://doi.org/10.1038/s41388-024-02940-6

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