ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1675373
This article is part of the Research TopicEpithelial-Mesenchymal Transition (EMT) in Endocrine Disorders: Mechanisms, Hormonal Regulation, and Therapeutic PotentialView all articles
Knockdown of TOP2A Reverses Cisplatin 1 Resistance in Ovarian Cancer by Inhibiting 2 EMT via Ferroptosis Mediated by the 3 TP53/GPX4/SLC7A11 Axis 4
Provisionally accepted
- 1Fifth Clinical Medical College, Shanxi Medical University, Taiyuan,, China
- 2Institute of Upper Gastrointestinal Tumour Prevention and Treatment, Changzhi, China
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Introduction: Cisplatin resistance is a major challenge in ovarian cancer therapy, 19 particularly for high-grade serous ovarian cancer (HGSOC). DNA topoisomerase II α 20 (TOP2A) relates to cancer drug resistance, yet its role and molecular mechanisms in 21 ovarian cancer cisplatin resistance remain unclear. 22 Methods: TOP2A expression was detected in HGSOC tissues and cisplatin-resistant cells 23 (SKOV3-DDP, OVCAR3-DDP). Functional assays combined with TOP2A knockdown 24 evaluated cisplatin sensitivity and malignant phenotypes (proliferation, invasion, 25 migration) in resistant cells. RNA-seq and GEO cisplatin resistance dataset (GSE214302) 26 validated TOP2A ' s role in cisplatin resistance, prognostic value, and associations with 27 TP53, GPX4, SLC7A11. Molecular docking/Co-IP confirmed TOP2A-TP53 interaction. 28 Fer-1 and TP53 knockdown clarified TP53/GPX4/SLC7A11 axis regulation of ferroptosis 29 and EMT, and an in vivo xenograft tumor model validated these findings. 30 Results: TOP2A is highly expressed in HGSOC tissues and cisplatin-resistant cells, with 31 high levels strongly associated with tumor progression (advanced stage, high grade, 32 lymph node metastasis) and poor prognosis. RNA-seq shows TOP2A correlates with TP53, 33 GPX4, SLC7A11.GEO dataset analysis confirms all four associate with cisplatin 34 resistance. SLC7A11 and TOP2A are effective resistance biomarkers, and high TOP2A 35 predicts shorter progression-free survival. Molecular assays verify direct TOP2A-TP53 36 interaction. Functional experiments reveal TOP2A knockdown enhances cisplatin 37 sensitivity, inhibits malignancy, activates ferroptosis, and suppresses EMT via the 38 TP53/GPX4/SLC7A11 axis. This effect is reversed by Fer-1 or TP53 knockdown, with 39 mechanisms validated in vivo. 40 Conclusion: TOP2A represents a potential prognostic biomarker and therapeutic target 41 for cisplatin resistance in ovarian cancer (OC), as it regulates ferroptosis and EMT via the 42 TP53/GPX4/SLC7A11 axis, which is mediated by its direct interaction with TP53. This 43 thus provides a novel direction for treating cisplatin-resistant OC.
Keywords: TOP2A, cisplatin resistance, ovarian cancer, ferroptosis, EMT, TP53
Received: 29 Jul 2025; Accepted: 10 Oct 2025.
Copyright: © 2025 Xinyue, Wang, Liu, Han, Qin, Wang, Gao, Li and Suo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yuping Suo, yupingsuo123@163.com
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