The role of hepatocyte growth factor/scatter factor in hepatoblastoma and hepatocellular carcinoma progression

Hepatocyte growth factor/scatter factor (HGF/SF) is a ubiquitously expressed molecule that elicits pleiotropic functions on epithelial cells, including mitogenic, motogenic, differentiating, angiogenic, and morphogenic effects. The receptor for HGF/SF is c-Met, a product of the proto-oncogene c-met, which is abundantly expressed in many tumors, rendering them highly receptive for HGF/SF signals. In hepatoblastoma (HB) and hepatocellular carcinoma (HCC), a high relapse incidence and post-operative residual tumor growth can be detected, when the serum levels of HGF/SF are markedly elevated, suggesting a link between this molecule and tumor malignancy. Although HB and HCC are two distinct subtypes of primary tumors arising from liver parenchymal cells and thus differ by many histo-clinical characteristics, comparative analysis of the impact of HGF/SF on these tumors may provide some clues on the oncogenic pathways leading to liver tumor progression. The results of this study demonstrate that HGF/SF mediates cytoprotective functions against the apoptotic inducers cisplatin, camptothecin, and starvation in a phosphoinositide 3-kinase (PI3K)dependent manner, thereby contributing to chemotherapy resistance. Differences between HB and HCC cells regarding the sensitivity towards HGF/SF and HGF/SFstimulated cellular responses were observed and are associated with c-Met expression. Furthermore, our experiments demonstrate that HGF/SF is a potent inducer of cell scattering and migration. HGF/SF triggers scattering of epithelial cells by upregulating the expression of Snail, a transcriptional repressor involved in epithelial-mesenchymal transition (EMT). Snail, which represses for example the expression of E-cadherin and claudin-3, is required for HGF/SF-induced cell scattering, since shRNA-mediated ablation of Snail expression prevents this process. HGF/SF-induced upregulation of Snail transcription involves activation of the mitogen-activated protein kinase (MAPK) pathway and requires the activity of early growth response factor (Egr)-1. Thus, HGF/SF plays a critical role in cell scattering, migration, and invasion. Together, these findings highlight the importance of HGF/SF in tumor cell survival and tumor progression and suggest that it should be considered as a candidate for therapeutic strategies.