Tumor-associated macrophages facilitate oral squamous cell carcinomas migration and invasion by MIF/NLRP3/IL-1beta circuit: A crosstalk interrupted by melatonin.

Invasion and migration are significant challenges for treatment of oral squamous cell carcinomas (OSCCs). Tumor-associated macrophages (TAMs) interact with cancer cells and are involved in tumor progression. Our recent study demonstrated that melatonin inhibits OSCC invasion and migration; however, the mechanism by which melatonin influences crosstalk between TAMs and OSCCs is poorly understood. In this study, a co-culture system was established to explore the interactions between human monocytic cells (THP-1 cells) and human tongue squamous cell carcinoma cells (SCC-15 cells). The results were verified using monocyte-derived macrophages (MDMs) isolated and differentiated from primary peripheral blood mononuclear cells. In vivo, assays were performed to confirm the anticancer effects of melatonin. SCC-15 cells co-cultured with THP-1 cells or MDMs exhibited increased migration and invasion, which was reversed by melatonin. Co-culture also increased the expression of macrophage migration inhibitory factor (MIF), CD40, CD163 and IL-1beta, and these changes were also reversed by melatonin. Moreover, IL-1beta secretion in THP-1 cells was MIF- and NLR family pyrin domain-containing 3 (NLRP3)-dependent, and treated with IL-1beta enhanced the invasion and migration of SCC-15 cells. Furthermore, melatonin treatment significantly decreased tumor volumes and weights, and tumors from mice treated with melatonin had lower levels of MIF, NLRP3, and IL-1beta than tumor from control mice. These results demonstrate that macrophages facilitate the progression of OSCCs by promoting the MIF/NLRP3/IL-1beta signaling axis, which can be interrupted by melatonin. Therefore, melatonin could act as an alternative anticancer agent for OSCCs by targeting this signaling axis.