The increased matrix stiffness caused by LOXL2 activates Piezo1 channels to promote the migration and invasion of cervical cancer cells

Background: Lymph node metastasis in cervical Cancer (CC) is a significant contributor to mortality associated with this disease. Notably, CC with lymph node metastasis exhibits greater stiffness upon palpation compared to CC without such metastasis. Lysyl oxidase-like 2 (LOXL2), a member of the Lysyl Oxidase (LOX) family, is capable of catalyzing the crosslinking of extracellular matrix (ECM) components. Additionally, Piezo1 is a mechanosensitive ion channel protein in mammals that can detect mechanical stimuli and regulate cellular behavior, making it a critical protein in tumor development. This prompted us to explore the relationship between the progression of CC and the roles of Piezo1 from a biomechanical perspective.

Methods: Young's modulus of tissue was measured by atomic force microscope (AFM). The Collagen coated polyacrylamide hydrogel (PA gel) system was prepared to mimic the soft and stiff substrates in vitro. The efficacy of Piezo1 was evaluated in vitro using transwell assay, immunofluorescence, and western blot analysis. Experiments in vivo have also confirmed the effect of matrix hardness on CC progression and on Piezo1.

Results: We quantitatively confirmed that CC with lymph node metastases was more rigid and more abundant in connective tissue proliferation than CC without lymph node metastases, and further demonstrated that stromal stiffness significantly modulated CC progression. Remarkably, Piezo1 has been identified as a potent mechanosensitive gene capable of responding to environmental stiffness, thereby mediating stiffness-regulated CC progression through the regulation of the Piezo1 channel protein. In vivo, the LOXL2 inhibitor not only effectively inhibited the growth of tumors in vivo, but also reduced the expression of Piezo1 in tumors by reducing the matrix stiffness.

Conclusion: These data suggest that targeting extracellular matrix (ECM) stiffness may hinder the progress of CC. Notably, targeting Piezo1 may offer promising clinical value for CC therapy.

Cervical cancer; Invasion; Matrix stiffness; Migration; Piezo1.