PLOD2-driven IL-6/STAT3 signaling promotes the invasion and metastasis of oral squamous cell carcinoma via activation of integrin β1

We previously reported that high expression of procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) leads to stabilization and plasma membrane translocation of integrin β1 to promote the invasion and metastasis of oral squa- mous cell carcinoma (SCC). The present study aimed to further understand the relationship between PLOD2-integrin β1 signaling and the tumor microenvironment. This study provided further advanced insights indicating that elevated interleukin (IL)-6 in the tumor microenvironment acts as a key molecule that triggers PLOD2-integrin β1 axis-derived acceleration of tumor invasion and metastasis. It was found using the dual-luciferase reporter assay system that signal transducer and activator of transcription 3 (STAT3) activation by IL-6 was essential for increasing the expression levels of PLOD2 through direct activation of the PLOD2 promoter in oral SCC, whereas IL-6 stimulation did not contribute to integrin β1 expression or the subsequent maturation process towards a functional form on the plasma membrane. Furthermore, the expression of IL-6 in oral SCC tissues was mainly observed in the tumor stroma. Finally, with double immunofluorescence staining, it was found that IL-6 expres- sion occurred in CD163-positive M2 macrophages distributed around the tumor nest. These results combined with our previous results indicate that as IL-6 significantly increases STAT3-mediated PLOD2 promoter activity, IL-6 released by M2-type tumor-associated macrophages is a crucial factor that promotes PLOD2-integrin β1 axis-enhanced invasion and metastasis of oral SCC cells.