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Hepatocyte growth factor (HGF) activator inhibitor type‐1 (HAI‐1), encoded by the  SPINT1  gene, is a transmembrane protease inhibitor that regulates membrane‐anchored serine proteases, particularly matriptase. Here, we explored the role of HAI‐1 in tongue squamous cell carcinoma (TSCC) cells. An immunohistochemical study of HAI‐1 in surgically resected TSCC revealed the cell surface immunoreactivity of HAI‐1 in the main portion of the tumor. The immunoreactivity decreased in the infiltrative front, and this decrease correlated with enhanced lymphatic invasion as judged by podoplanin immunostaining. In vitro homozygous deletion of  SPINT1  (HAI‐1KO) in TSCC cell lines (HSC3 and SAS) suppressed the cell growth rate but significantly enhanced invasion in vitro. The loss of HAI‐1 resulted in enhanced pericellular activities of proteases, such as matriptase and urokinase‐type plasminogen activator, which induced activation of HGF/MET signaling in the co‐culture with pro‐HGF‐expressing fibroblasts and plasminogen‐dependent plasmin generation, respectively. The enhanced plasminogen‐dependent plasmin generation was abrogated partly by matriptase silencing. Culture supernatants of HAI‐1KO cells had enhanced potency for converting the proform of vascular endothelial growth factor‐C (VEGF‐C), a lymphangiogenesis factor, into the mature form in a plasminogen‐dependent manner. Furthermore, HGF significantly stimulated VEGF‐C expression in TSCC cells. Orthotopic xenotransplantation into nude mouse tongue revealed enhanced lymphatic invasion of HAI‐1KO TSCC cells compared to control cells. Our results suggest that HAI‐1 insufficiency leads to dysregulated pericellular protease activity, which eventually orchestrates robust activation of protease‐dependent growth factors, such as HGF and VEGF‐C, in a tumor microenvironment to contribute to TSCC progression.

Insufficiency of hepatocyte growth factor activator inhibitor‐1 confers lymphatic invasion of tongue carcinoma cells