Linagliptin's impact on lymphatic barrier and lymphangiogenesis in oral cancer with high glucose.

OBJECTIVES: Uncertainties remain regarding the effect of elevated glucose levels on lymphatic metastasis of cancer cells. Our study elucidated the mechanisms linking high glucose to lymphangiogenesis and lymphatic barrier-related factors and investigated the protective role of linagliptin against lymphatic barrier dysfunction. MATERIALS AND METHODS: A CAL-27-LEC co-culture system was established. Sodium fluorescein permeability assay observed lymphatic endothelial cell permeability. Western blotting and RT-qPCR detected protein and mRNA expression under different conditions, respectively. CCK-8, scratch wound healing, and transwell assays revealed cell migration and proliferation. Tube formation experiment tested capacity for endothelial tube formation. Immunohistochemical staining analyzed tissue sections from 43 oral cancer individuals with/without diabetes. RESULTS: In high-glucose co-culture system, we observed increased lymphatic barrier permeability and decreased expression of ZO-1 and occludin, two tight-junction proteins; conversely, the expression of PAR2, a high permeability-related protein, was increased. Following linagliptin treatment, the expression levels of VEGF-C, VEGFR-3, and PAR2 decreased, while those of ZO-1 and occludin increased. Considerably higher levels of LYVE-1 expression in individuals with diabetes than in those without diabetes. CONCLUSIONS: By ameliorating the high glucose-induced disruption of the lymphatic endothelial barrier, linagliptin may reduce lymphangiogenesis and exhibit an inhibitory effect on lymphatic metastasis in oral cancer patients with diabetes.

Downregulation of VAP-1 in OSCC suppresses tumor growth and metastasis via NF-κB/IL-8 signaling and reduces neutrophil infiltration.

BACKGROUND: Vascular adhesion protein-1 (VAP-1) is believed to play a role in inflammation. Studies have suggested that VAP-1-mediated activation of inflammation is dependent on NF-κB, leading to secretion of the interleukin (IL)-8; however, no reports have addressed the association between VAP-1 and NF-κB/IL-8 signaling in oral squamous cell carcinoma (OSCC). This study aimed to investigate the role of VAP-1 in OSCC and further explore whether VAP-1 is involved in the regulation of neutrophil infiltration in the tumor microenvironment (TME). METHODS: Immunochemistry staining was used to observe VAP-1 expression. CCK-8 and Transwell assays were used to measure cell proliferation, migration, and invasion. OSCC xenograft mouse models were used for in vivo verification of the VAP-1 function. The expression of NF-κB and IL-8 were determined by qRT-PCR and western blot. ELISA for IL-8 was also conducted. The relationship between VAP-1 expression and neutrophil infiltration was analyzed by immunofluorescence. RESULTS: VAP-1 was overexpressed in human OSCC tissues. Downregulation of VAP-1 suppressed OSCC cells proliferation, migration, and invasion in vitro and inhibited tumor proliferation and metastasis in vivo. Additionally, downregulation of VAP-1 inhibited NF-κB/IL-8 signaling in vitro and in vivo. VAP-1 expression was positively correlated with neutrophil infiltration in human OSCC tissues. Moreover, blocking VAP-1 decreased neutrophil infiltration by reducing IL-8 production. CONCLUSIONS: VAP-1 downregulation in OSCC suppresses tumor growth and metastasis by inhibiting NF-κB/IL-8 signaling and reducing neutrophil infiltration in the TME, suggesting that VAP-1 may be a potential therapeutic target for OSCC.