The detection of the effect of HGF/c-met pathway on tumor cell microenvironment interactions and cell behaviors like adhesion, proliferation, motility, invasion, metastasis in hepatocellular carcinoma cell lines

Liver carcinogenesis is associated with changes in the coordinated actions of severalmolecules including growth factors, extracellular matrix (ECM) proteins, proteoglycans, andtheir ligands. There is increasing amount of evidence that a close collaboration betweengrowth factors and ECM in several biological processes such as cell adhesion, migration andproteolysis are regarded as important steps in the development of invasion and metastasis.This may be particularly important for the liver carcinogenesis, due to HCC cells mainly growin trabecular structures that are surrounded by tissue with a high content of ECM proteins andproteoglycans as well as growth factors such as Hepatocyte Growth Factor (HGF/SF).In this study, we examined the effects of HGF and/or ECM components on biologicalactivities of HCC cells induced by HGF. We have shown that collagen IV and fibronectinincreased cell adhesion and motility, but not cell proliferation, whereas laminin increased cellproliferation without changing cell adhesion and motility. HGF stimulation increased all ofthese biological effects. Heparin modestly decreased both basal and HGF induced adhesion,proliferation and motility. Microarray analysis showed that in the presence of heparin andHGF the expression of 47 genes increases whereas expression of 28 genes decreasescompared to heparin alone. Treatment with fibronectin, laminin and heparin decreasedintegrin expressions by 1.2-6 fold. In the case of HGF treatment this decrease extend to 2-9fold. Integrin expression was increased two fold by collagen IV treatment. Two to three foldincrease in integrin expression was obtained with HGF stimulation.These findings support the role of HGF and/or ECM components in the behaviors ofHCC cells. It may also help to identify the association of HGF signaling and c-Met, integrinsand their ligands in HCC cells.