Matrix stiffness regulates NPC invasiveness by modulating a mechanoresponsive TRPV4-Nox4-IL-8 signaling axis

Matrix stiffness is a critical determinant of tumorigenesis and cancer progression. Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive calcium channel, regulates angiogenesis and stromal stiffness in various tumors. However, it is unclear whether matrix stiffness regulates the invasiveness of nasopharyngeal carcinoma (NPC) cells through TRPV4. In this study, we found that increased matrix stiffness of NPC tissues correlated with advanced tumor stages. Furthermore, simulation of high matrix stiffness in vitro upregulated TRPV4, and increased the migration, invasion, and epithelial mesenchymal transition (EMT) of NPC cells. Knockdown or pharmacological inhibition of TRPV4 significantly suppressed the calcium influx in NPC cells, and inhibited their invasiveness and EMT under high-stiffness conditions. Mechanistically, TRPV4 modulated the invasiveness of NPC cells in response to matrix stiffness via the NOX4/IL-8 axis. Notably, TRPV4 and IL-8 levels were significantly increased in the high-stiffness NPC tissues, and showed a positive correlation. Taken together, matrix stiffness promotes the malignant progression of NPC cells through the activation of the TRPV4/NOX4/IL-8 axis, which could be explored further as a potential target for NPC therapy.