The cooperative role of S1P3 with LYVE-1 in LMW-HA-induced lymphangiogenesis.

Lymphangiogenesis, the formation of new lymph vessels, plays a significant role in the development and metastasis of various cancers. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA) promotes lymphangiogenesis. However, the underlying mechanisms are poorly defined. In this study, using immunofluorescence and co-immunoprecipitation, we found that LMW-HA increased the colocalization of lymphatic vessel endothelial HA receptor (LYVE-1) and sphingosine 1-phosphate receptor (S1P3) at the cell surface. Silencing of either LYVE-1 or S1P3 decreased LMW-HA-mediated tube formation in lymphatic endothelial cells (LECs). Furthermore, silencing of either LYVE-1 or S1P3 significantly inhibited LMW-HA-induced tyrosine phosphorylation of Src kinase and extracellular signal-regulated kinase (ERK1/2). In summary, these results suggest that S1P3 and LYVE-1 may cooperate to play a role in LMW-HA-mediated lymphangiogenesis. This interaction may provide a useful target for the intervention of lymphangiogenesis-associated tumor progression.