Mast cell chymase promotes angiogenesis and lymphangiogenesis mediated by activation of melanoma inhibitory activity gene family members in oral squamous cell carcinoma

Mast cells (MCs) are present in the tumor stroma, and MCs that express the mast cell-specific proteases tryptase and chymase (MCTC) exhibit several tumor-related functions. It was previously reported that melanoma inhibitory activity (MIA) gene family members, including MIA, MIA2, and transport and Golgi organization protein 1 (TANGO), possess oncogenic functions in oral squamous cell carcinoma (OSCC). However, the relationships between MCTC, and clinicopathological characteristics and activation of the MIA gene family in OSCC remain unknown. In the present study, the functional roles of MCTC in patients with OSCC were investigated using immunohistochemistry and reverse transcription-quantitative PCR. In addition, the effects of extracellular chymase on oral cancer cells were examined. In patients with OSCC, MCTC density was significantly affected by tumor progression and nodal metastasis, and was correlated with vessel density. MCTC density was also correlated with MIA and MIA2 expression. In OSCC cells, extracellular chymase promoted the secretion of vascular endothelial growth factor family proteins, and the transmigration and adhesion of HSC3 cells to endothelial cells; knockdown of MIA, MIA2 and TANGO attenuated these effects. The present findings indicated that MCTC act as tumor-progressive factors in OSCC via the activation and secretion of MIA and MIA2, and the induction of angiogenesis and lymphangiogenesis.