Mechanistic Study of Matrix Stiffness Promoting Lymph Node Metastasis in Cervical Cancer by Regulating NETs Formation...

Area of Science:

• Oncology
• Biophysics
• Cell Biology

Background:

• Cervical cancer metastasis is linked to increased extracellular matrix stiffness.
• The role of matrix stiffness in regulating neutrophil extracellular traps (NETs) in cervical cancer is not fully understood.
• Piezo1 channels are mechanosensors involved in translating mechanical signals into cellular responses.

Purpose of the Study:

• To investigate the mechanism by which extracellular matrix stiffness regulates NETs formation in cervical cancer.
• To explore the role of the Piezo1 channel in this process.
• To identify potential therapeutic targets for advanced cervical cancer.

Main Methods:

• Atomic force microscopy and histochemical staining to assess matrix stiffness and protein expression in cervical cancer tissues.
• Polyacrylamide gel models for cell culture, transcriptome sequencing, and ELISA to analyze IL-8 expression.
• In vitro induction of NETs and assessment of their effects on lymphatic endothelial cells.
• In vivo studies using a TC-1 mouse model and Western blot/ELISA to analyze the Piezo1/NF-κB pathway.

Main Results:

• Metastatic cervical cancer tissues exhibit higher stiffness, increased α-SMA/Collagen I expression, and greater collagen content.
• High matrix stiffness activates the Piezo1/NF-κB pathway, leading to upregulated IL-8, NETs formation, and enhanced lymphatic endothelial cell migration and tube formation.
• Pharmacological inhibition of stiffness (BAPN) reduced tumor stiffness, inhibited metastasis, and decreased NETs in vivo.
• Piezo1 knockdown abrogated NF-κB activation and IL-8 upregulation.

Conclusions:

• Increased extracellular matrix stiffness in cervical cancer activates the Piezo1/NF-κB pathway, promoting IL-8 secretion and NETs formation.
• This process enhances lymphangiogenesis and cervical cancer metastasis.
• Targeting the Piezo1 pathway presents a promising strategy for treating advanced cervical cancer.