Modulation of the malignant behavior of tongue squamous cell carcinoma cells by matrix metallopeptidase 25 through the NF-κB pathway

Abstract

Objective. Accumulating evidence has implicated matrix metalloproteinases (MMPs) in the progression of human cancers. Matrix metallopeptidase 25 (MMP25) is a membrane-type MMP whose role in tumorigenesis and cancer development is not well understood. Here, we investigated the functions of MMP25 in tongue squamous cell carcinoma (TSCC). Methods. Gene expression was measured using real-time PCR and western blot. CCK-8 and Transwell assays were used to determine the proliferation, migration, and invasion of TSCC cells. An NK cell co-culture experiment was performed to evaluate the killing of TSCC cells by NK cells. Results. MMP25 had higher expression levels in TSCC tissues than in adjacent non-cancerous tissues. MMP25-overexpressing and MMP25-silenced TSCC cell lines were established by lentiviral transduction. Overexpression of MMP25 promoted proliferation, migration, and invasion of TSCC cells, whereas knockdown of MMP25 had opposite effects. MMP25 modulated the levels of proliferation- and apoptosis-related proteins (PCNA, cyclin D, cyclin B1, p27, and cleaved caspase 3 and 9) and upregulated two invasion-related MMPs (mature MMP2 and MMP9). Additionally, MMP25 promoted tumor growth of TSCC cells in athymic nude mice. Notably, MMP25 upregulated PD-L1 in TSCC cells, attenuated NK cell killing of TSCC cells, and inhibited the secretion of anti-tumor cytokines (TNF-α and IFN-γ). Furthermore, MMP25 promoted the nuclear translocation of NF-κB p65, suggesting that activation of NF-κB signaling may mediate the pro-tumor functions of MMP25 in TSCC. Conclusion. This study revealed a novel role for MMP25 in TSCC, highlighting the potential of MMP25 as a therapeutic target in TSCC.