title: Epigenetic Silencing of SPINT2 Promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma.
abstract: 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.
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachussetts, USA.
authors.forename: Soonyean
authors.initials: S
authors.lastname: Hwang
authors.affiliation: Department of Anatomy, BK21 Plus Program, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hye-Eun
authors.initials: HE
authors.lastname: Kim
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachussetts, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Min
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachussetts, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Raghunathan
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachussetts, USA.
authors.forename: Izabela P
authors.initials: IP
authors.lastname: Panova
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachussetts, USA.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Munshi
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachussetts, USA. Electronic address: ryub@bu.edu.
authors.forename: Byungwoo
authors.initials: B
authors.lastname: Ryu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D012697:Serine Endopeptidases; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: C000715470:MAS1 protein, human; D008562:Membrane Glycoproteins; D000090063:Proto-Oncogene Mas; C109148:SPINT2 protein, human; D017228:Hepatocyte Growth Factor; C081092:HGF activator; D012697:Serine Endopeptidases