Aberrant HGF-MET (
hepatocyte growth factor-met proto-oncogene) signaling activation via interactions with surrounding stromal cells in tumor microenvironment has significant roles in malignant
tumor progression. However, extracellular proteolytic regulation of HGF activation, which is influenced by the tumor microenvironment, and its consequential effects on
melanoma malignancy remain uncharacterized. In this study, we identified SPINT2 (
serine peptidase inhibitor Kunitz type 2), a proteolytic inhibitor of
hepatocyte growth factor activator (HGFA), which has a significant role in the suppression of the HGF-MET pathway and
malignant melanoma progression. SPINT2 expression is significantly lower in metastatic
melanoma tissues compared with those in early-stage primary
melanomas, which also corresponded with DNA methylation levels isolated from tissue samples. Treatment with the
DNA-hypomethylating agent
decitabine in cultured
melanoma cells induced transcriptional reactivation of SPINT2, suggesting that this gene is epigenetically silenced in
malignant melanomas. Furthermore, we show that ectopically expressed SPINT2 in
melanoma cells inhibits the HGF-induced MET-AKT (v-Akt murine
thymoma viral oncogene) signaling pathway and decreases malignant phenotype potential such as cell motility and invasive growth of
melanoma cells. These results suggest that SPINT2 is associated with
tumor-suppressive functions in
melanoma by inhibiting an extracellular signal regulator of HGF, which is typically activated by
tumor-stromal interactions. These findings indicate that epigenetic impairment of the tightly regulated
cytokine-receptor communications in tumor microenvironment may contribute to malignant
tumor progression.