Sphingosine kinases negatively regulate the expression of matrix metalloproteases ( and ) and their inhibitor genes via sphingosine 1-phosphate in extravillous trophoblasts.

PURPOSE

Extracellular matrix remodeling is essential for extravillous trophoblast (EVT) cell migration and invasion during placental development and regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteases (TIMPs). Sphingosine kinases (SPHK1 and SPHK2) synthesize sphingosine-1-phosphate (S1P), which works either intracellularly or extracellularly via its receptors S1PR1-5 in an autocrine or paracrine manner. The role of SPHKs/S1P in regulating the expression of MMPs and TIMPs in EVT is mostly unknown and forms the primary objective of the study.

METHODS

HTR-8/SVneo cells were used as a model of EVT. To inhibit the expression of SPHKs, cells were treated with specific inhibitors, SK1-I and SKI-II, or gene-specific siRNAs. The expressions of were estimated by qPCR.

RESULTS

We demonstrated that , , and were highly expressed in HTR-8/SVneo cells. We found that treatment of cells with SK1-I, SKI-II, and knockdown of or increased the expression of , , and . The addition of extracellular S1P inhibits the upregulation of and in treated cells.

CONCLUSIONS

SPHKs negatively regulate the expression of , , and . The level of intracellular S1P acts as a negative feedback switch for , , and expression in EVT cells.