5 research outputs found
Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells
International audienceBackgroundWe previously demonstrated that the CC-chemokine Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES)/CCL5 exerts pro-tumoral effects on human hepatoma Huh7 cells through its G protein-coupled receptor, CCR1. Glycosaminoglycans play major roles in these biological events.MethodsIn the present study, we explored 1/ the signalling pathways underlying RANTES/CCL5-mediated hepatoma cell migration or invasion by the use of specific pharmacological inhibitors, 2/ the role of RANTES/CCL5 oligomerization in these effects by using a dimeric RANTES/CCL5, 3/ the possible involvement of two membrane heparan sulfate proteoglycans, syndecan-1 (SDC-1) and syndecan-4 (SDC-4) in RANTES/CCL5-induced cell chemotaxis and spreading by pre-incubating cells with specific antibodies or by reducing SDC-1 or -4 expression by RNA interference.Results and conclusionThe present data suggest that focal adhesion kinase phosphorylation, phosphoinositide 3-kinase-, mitogen-activated protein kinase- and Rho kinase activations are involved in RANTES/CCL5 pro-tumoral effects on Huh7 cells. Interference with oligomerization of the chemokine reduced RANTES/CCL5-mediated cell chemotaxis. This study also indicates that SDC-1 and -4 may be required for HepG2, Hep3B and Huh7 human hepatoma cell migration, invasion or spreading induced by the chemokine. These results also further demonstrate the involvement of glycosaminoglycans as the glycosaminoglycan-binding deficient RANTES/CCL5 variant, in which arginine 47 was replaced by lysine, was devoid of effect.General significanceThe modulation of RANTES/CCL5-mediated cellular effects by targeting the chemokine-syndecan interaction could represent a new therapeutic approach for hepatocellular carcinoma
Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells
International audienceThe aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant proteinâ1 (MCPâ1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCPâ1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cellâconditioned medium (LI90âCM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCPâ1/CCL2âdepleted LI90âCM was used. We showed that MCPâ1/CCL2 induces Huh7 cell migration and invasion through its Gâproteinâcoupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCPâ1/CCL2 concentrations. MCPâ1/CCL2's chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)â2 and MMPâ9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by ÎČâDâxyloside treatment of cells and by antiâsyndecanâ1 and â4 antibodies. Finally, we developed a 3âdimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCPâ1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatomaâmyofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblastâderived MCPâ1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma