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

• Published in: Oral diseases Vol. 30; no. 7; pp. 4195 - 4208
• Main Authors: Wang, Hongyu, She, Xiao, Xu, Qiongdong, Zhou, Xingyu, Tang, Qinchao, Wei, Huakun, Huang, Tianjing, Liang, Feixin
• Format: Journal Article
• Language: English
• Published: Denmark Wiley Subscription Services, Inc 01.10.2024
• Subjects: Cell culture; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell permeability; Cell Proliferation - drug effects; Cholecystokinin; Coculture Techniques; Diabetes; Diabetes mellitus; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Gene expression; Glucose; Glucose - metabolism; high glucose; Humans; linagliptin; Linagliptin - pharmacology; Linagliptin - therapeutic use; lymphangiogenesis; Lymphangiogenesis - drug effects; lymphatic metastasis; Metastases; Metastasis; Mouth Neoplasms - drug therapy; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Occludin - metabolism; Oral cancer; oral squamous cell carcinoma; Permeability; Permeability - drug effects; tight‐junction; Vascular endothelial growth factor; Vascular Endothelial Growth Factor C - metabolism; Vascular Endothelial Growth Factor Receptor-3 - metabolism; Vascular endothelial growth factor receptors; Vesicular Transport Proteins - metabolism; Western blotting; Wound healing; Zonula Occludens-1 Protein - metabolism; lymphangiogenesis; oral squamous cell carcinoma; linagliptin; high glucose; lymphatic metastasis; tight‐junction
• ISSN: 1354-523X; 1601-0825; 1601-0825
• DOI: 10.1111/odi.14893

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.