Dipeptidyl peptidase-IV (DPP-IV) inhibitors are used to control blood glucose levels in patients with type 2 diabetes. However, the influence of DPP-IV inhibitors on malignant tumors remains unknown. The present study aimed to investigate the effect of the DPP-IV inhibitor saxagliptin on thyroid carcinoma cells. Transwell assays and a nude mouse lung metastasis model were used to evaluate the invasion and metastasis of thyroid carcinoma cells. Western blotting was used to determine the protein levels of migration and invasion-related molecules. We tested the expression and distribution of nuclear factor, erythroid 2 like 2 (NRF2) in thyroid carcinoma cells with and without saxagliptin. Furthermore, we silenced NRF2 and observed saxagliptin's effect on migration and invasion. Quantitative real-time reverse transcription PCR (qRT-PCR) and western blotting were then used to measure the expression of NFR2's downstream molecules (heme oxygenase 1 (HO1), matrix metalloproteinase 2 (MMP2), and vascular endothelial growth factor (VEGF)). A luciferase reporter assay was used to validate whether NRF2 could regulate the transcriptional activity of the HO1 promoter. Saxagliptin enhanced the migratory and invasive ability of thyroid carcinoma cells. MMP2 and VEGF levels were also elevated by saxagliptin treatment. We found that saxagliptin treatment increases the nuclear and cytoplasmic accumulation NRF2. Silencing NRF2 abolished the effect of saxagliptin on migration and invasion. Accordingly, NRF2 silencing downregulated HO1, MMP2, and VEGF levels. The luciferase assay showed that NRF2 activated transcription from the HO1 promoter. Saxagliptin could promote this transcriptional activity by upregulating NRF2. Saxagliptin enhanced the migratory and invasive ability of human thyroid carcinoma cells, as well as the expression of MMP2 and VEGF, by activating the NRF2/HO1 pathway.
Keywords: Cell movement; Dipeptidyl peptidase-IV inhibitors; NF-E2 transcription factor; Neoplasm invasiveness; Papillary; Thyroid cancer.