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Hypoxia can induce c‐Met expression in glioma cells and enhance SF/HGF‐induced cell migration

The c‐Met receptor and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly overexpressed in malignant gliomas. Signaling through c‐Met as well as exposure to hypoxia can stimulate glioma cell migration and invasion. In several cancer cell types, hypoxia was shown to activate the c‐met promoter, which contains hypoxia inducible factor‐1 (HIF‐1) binding sites. We hypothesized that hypoxia might upregulate c‐Met also in glioma cells. Analyzing 18 different glioblastoma cell lines and 10 glioblastoma primary cultures, we found that in 50% of both the cell lines and the primary cultures c‐Met protein levels were increased following exposure to hypoxia. Upregulation of c‐met in response to hypoxia was also detected at the transcriptional level. In all primary cultures and in 16 of the 18 cell lines (89%), HIF‐1α levels were increased by hypoxia. Transfection of siRNA against HIF‐1α abgrogated the hypoxic induction of c‐Met, suggesting that c‐Met expression is upregulated by a HIF‐1α‐dependent mechanism. Hypoxia sensitized glioblastoma cell lines which showed hypoxic induction of c‐Met to the motogenic effects of SF/HGF. These findings suggest that approximately half of all human glioblastomas respond to hypoxia with an induction of c‐Met, which can enhance the stimulating effect of SF/HGF on tumor cell migration. © 2007 Wiley‐Liss, Inc.