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2015 ; 135
(9
): 2283-2291
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Epigenetic Silencing of SPINT2 Promotes Cancer Cell Motility via HGF-MET Pathway
Activation in Melanoma
#MMPMID25910030
Hwang S
; Kim HE
; Min M
; Raghunathan R
; Panova IP
; Munshi R
; Ryu B
J Invest Dermatol
2015[Sep]; 135
(9
): 2283-2291
PMID25910030
show ga
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.