[Show abstract][Hide abstract] ABSTRACT:
The growth factor hepatocyte growth factor (HGF), also known as scatter factor, and its tyrosine kinase receptor c-Met play important roles in medulloblastoma malignancy. The transcription factor c-Myc is another contributor to the malignancy of these most common pediatric brain tumors. In the present study, we observed strong morphological similarities between medulloblastoma xenografts overexpressing HGF and medulloblastoma xenografts overexpressing c-Myc. We therefore hypothesized a biologically significant link between HGF/c-Met and c-Myc in medulloblastoma malignancy and studied the molecular and functional interactions between them. We found that HGF induces c-Myc mRNA and protein in established and primary medulloblastoma cells. HGF regulated c-Myc levels via transcriptional and post-transcriptional mechanisms as evidenced by HGF induction of c-Myc promoter activity and induction of c-Myc protein levels in the setting of inhibited transcription and translation. We also found that HGF induces cell cycle progression, cell proliferation, apoptosis and increase in cell size in a c-Myc-dependent manner. Activation of MAPK and PI3K, inhibition of GSK-3beta and translocation of beta-catenin to the nucleus as well as Tcf/Lef transcriptional activity were involved in mediating c-Myc induction by HGF. Induction of Cdk2 kinase activity was involved in mediating the cell cycle progression effects, and downregulation of Bcl-XL was involved in mediating the proapoptotic effects of HGF downstream of c-Myc. All molecules that mediated the effects of HGF on c-Myc expression, cell proliferation and apoptosis were expressed in human large-cell medulloblastoma tissues. We therefore established for the first time a functional cooperation between HGF/c-Met and c-Myc in human medulloblastoma and elucidated the molecular mechanisms of this cooperation. The findings provide a potential explanation for the high frequency of c-Myc overexpression in medulloblastoma and suggest a cooperative role for c-Met and c-Myc in large-cell anaplastic medulloblastoma formation.