Mechanosensitive TRPV4 Trafficking Drives TGF-Β-Mediated Mesenchymal Transition in Colorectal Cancer

Abstract

Mechanosensitive TRPV4 Trafficking Drives TGF-Β-Mediated Mesenchymal Transition in Colorectal Cancer

Abstract

Background and Purpose Epithelial-to-mesenchymal transition (EMT) enhances the invasive potential of cancers, significantly affecting survival rates in metastatic disease. TGF-β, a potent EMT regulator enriched in colon cancer (CRC), is influenced by bioelectric and biophysical forces. While some ion channels and mechanical forces are linked, TGF-β-coupled mechanosensing mechanisms in CRC remain poorly understood. This study investigates the mechanosensitive ion channel TRPV4 and its role in TGF-β-induced EMT, focusing on channel trafficking and its functional implications in CRC. Methods We analyzed mechanosensitive ion channels mRNA expressions in CRC stages and evaluated their association with survival through Kaplan-Meier analysis. Correlations were analyzed with mesenchymal gene sets, soluble factors, and TGF-β signaling. Immunofluorescence was used to visualize TRPV4 localization in untreated and 10 ng/mL TGF-β1-treated colon cell lines. Functional studies involved co-stimulation with TGF-β1 and TRPV4 modulators (GSK101 and HC-067047) to assess EMT-related changes. Results TRPV4 mRNA is elevated in CRC, with TRPV4-001 as the predominant isoform. High expression correlated with poor survival, EMT signatures, and TGF-β1 signaling . TGF-β1 induced out-of-nucleus TRPV4 translocation. TRPV4 inhibition reduced TGF-β-induced N-cadherin expression, mitigating EMT. Conclusion TRPV4 regulates TGF-β-induced EMT through trafficking mechanisms. Its inhibition presents anti-metastatic potential, identifying TRPV4 as a therapeutic target in CRC.

Keywords

• TRPV4
• TGF-β
• EMT
• Translocation
• Ion channel
• Mechanosensitive

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