Journal Article

Neutrophil elastase promotes low molecular weight cyclin E1 formation to accelerate osteosarcoma proliferation

Xu, Jiuhui, Ren, Tingting, Wei, Ran, Tang, Xiaodong, Zeng, Fanwei, Shi, Qianyu

2025

Overview

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 is upregulated in osteosarcoma. In this study, we identified a cytoplasmic, low molecular weight cyclin E1 isoform (LMW-cyclin E1) in osteosarcoma that is significantly associated with poor patient outcomes. We collected RNA sequencing data to analyze the cyclin E1 ( ) expression and performed Western blot assay, immunofluorescence, and 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. Small interfering RNA and plasmids were constructed to regulate neutrophil elastase (ELA2) expression to explore the 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 between neutrophil infiltration and OS progression was analyzed in 34 primary OS tissues and 33 OS lung metastasis tissues. Mechanistically, we found that 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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / Antibodies / Antigens / Bone cancer / Bone Neoplasms - genetics / Bone Neoplasms - immunology / Bone Neoplasms - metabolism / Bone Neoplasms - pathology / Cancer therapies / Cell culture / Cell Line, Tumor / Cell Proliferation / Cyclin E - genetics / Cyclin E - metabolism / cyclin E1 / Elastase / Female / Gene Expression Regulation, Neoplastic / Genes / Humans / Immunofluorescence / Immunohistochemistry / Immunology / Infiltration / Kinases / Laboratory animals / Leukocyte Elastase - genetics / Leukocyte Elastase - metabolism / Leukocytes (neutrophilic) / Lung Neoplasms - secondary / Male / Malignancy / Medical prognosis / Metastases / Metastasis / Mice / Mice, Inbred BALB C / Molecular Weight / NETs / neutrophil / neutrophil elastase/ELA2 / Neutrophil Infiltration / Neutrophils / Neutrophils - immunology / Neutrophils - metabolism / Oncogene Proteins - genetics / Oncogene Proteins - metabolism / Osteosarcoma / Osteosarcoma - genetics / Osteosarcoma - immunology / Osteosarcoma - metabolism / Osteosarcoma - mortality / Osteosarcoma - pathology / Plasmids / Proteins / siRNA / Software / Tumors