Tumor-associated neutrophils (TANs) promote metastasis of multiple cancers, including oral squamous cell carcinoma (OSCC). Melatonin (Mel) reportedly exerts anti-metastatic effects on OSCC. However, little is known about the anti-OSCC effects of Mel involved in TANs. In this study, intensive infiltration of TANs was positively associated with advanced stage, lymphatic metastasis, and poor prognosis of OSCC. Moreover, Mel reduced the survival and migration of OSCC-associated neutrophils. Mechanistically, Mel suppressed the TAN release of C-X-C motif chemokine ligand 8, C-C motif chemokine ligand 2 (CCL2), CCL4, and matrix metalloproteinase-9 by blockage of p38 MAPK and Akt signaling. Mel-fostered TANs decreased the migration and invasion of OSCC cells and reduced tube formation in vitro. Additionally, Mel-hampered pro-motility and pro-angiogenesis effects of TANs were dependent on MMP-9 suppression in OSCC. Overall, The beneficial roles of melatonin in retarding OSCC metastasis were implicated with inhibition of TANs.
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