ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1647913
This article is part of the Research TopicImmune-Cancer Cell InteractionView all 10 articles
Neutrophil elastase promotes low molecular weight cyclin E1 formation to accelerate osteosarcoma proliferation ・Authors' names
Provisionally accepted
- Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
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Introduction：Osteosarcoma (OS) is the most common primary bone malignancy, characterized by aggressive local invasion and a high propensity for metastasis. We previously reported that cyclin E1 was upregulated in osteosarcoma. In this study, we identified a cytoplasmic low molecular weight cyclin E1isoform (LMW-cyclin E1) in osteosarcoma that is significantly associated with poor patient outcomes. Methods：We collected the RNA sequencing data to analyze the CCNE expression, and performed Western blot assay, immunofluorescence, immunohistochemistry staining to validate cyclin E1 expression in OS. We also analyzed the correlation between its expression levels and the overall and progression-free survival rates of patients with OS. The small interference RNA and plasmids were constructed to regulate neutrophils elastase (ELA2) expression to explore the formation mechanism of low molecular weight cyclin E1 formation in OS. Neutrophils isolated from healthy donors were cocultured with OS cells to test the function of ELA2, and its effect was further validated in BALB/c mice. The relationship of neutrophils infiltration with OS progression was analyzed in 34 primary OS tissues and 33 OS lung metastasis tissues. Results and discussion: Mechanistically, we found that neutrophil elastase (ELA2), primarily derived from tumor-associated neutrophils, cleaves full-length cyclin E1 to generate LMW-cyclin E1, which accelerates OS proliferation. Moreover, neutrophil infiltration was associated with OS lung metastasis. OS cells also induced neutrophil extracellular trap formation, which further amplified ELA2 release. Depleting neutrophils or inhibiting ELA2 significantly suppressed OS malignancy. Hence, targeting neutrophil-osteosarcoma crosstalk may be a potential novel therapeutic strategy.
Keywords: cyclin E1, NETs, Neutrophil, neutrophil elastase/ELA2, Osteosarcoma
Received: 16 Jun 2025; Accepted: 07 Aug 2025.
Copyright: © 2025 Xu, Shi, Zeng, Ren, Wei and Tang. 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:
Ran Wei, Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
Xiaodong Tang, Musculoskeletal Tumor Center, Peking University People’s Hospital, Beijing, China
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