MMP-1-PAR1 axis mediates LPA-induced epithelial ovarian cancer (EOC) invasion

Objectives

MMP-1 is over-expressed in many cancers, with high expression often associated with poor survival. In the present study, we examined the expression of MMP-1 in EOC and its role in EOC invasion. Moreover, we evaluated the role of a newly identified MMP-1-protease activated receptor (PAR)-1 axis in LPA-induced EOC invasion.

Methods

MMP-1 and PAR1 mRNA expression in EOC cell lines was determined by real time PCR. MMP-1 mRNA expression in 96 normal and carcinoma ovarian tissue specimens was analyzed using a TissueScan real time PCR array. MMP-1 concentration in conditioned medium was measured by MMP-1 ELISA. PAR1 protein expression was detected by Western blotting. Cell invasion was evaluated by in vitro Matrigel invasion assay.

Results

In ovarian tumor tissues more MMP-1 expression was observed than in normal ovarian tissues (p < 0.05), and its expression correlated with tumor grade (grade 3 > grade 2 > grade 1). Human recombinant MMP-1 as well as serum free conditioned medium containing high levels of MMP-1 from DOV13 and R182 cells significantly promoted DOV13 cell invasion (p < 0.05), implicating a direct role of MMP-1 in EOC invasion. Moreover, MMP-1 induced DOV13 invasion was significantly blocked by PAR1 siRNA silencing. Furthermore, MMP-1 and PAR1 were both significantly induced by LPA (20 μM), and siRNA silencing of MMP-1 and PAR1 both significantly reduced LPA's invasion-promoting effect in DOV13 cells (p < 0.05).

Conclusions

Our results suggest that the MMP-1-PAR1 axis is involved in EOC invasion and at least partially mediates LPA-induced EOC invasion. Therefore, blocking MMP-1 or PAR1 may represent a new therapeutic option for metastatic EOC.