Abstract
The cโMet receptor and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly overexpressed in malignant gliomas. Signaling through cโMet as well as exposure to hypoxia can stimulate glioma cell migration and invasion. In several cancer cell types, hypoxia was shown to activate the cโmet promoter, which contains hypoxia inducible factorโ1 (HIFโ1) binding sites. We hypothesized that hypoxia might upregulate cโMet 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 cโMet protein levels were increased following exposure to hypoxia. Upregulation of cโmet in response to hypoxia was also detected at the transcriptional level. In all primary cultures and in 16 of the 18 cell lines (89%), HIFโ1ฮฑ levels were increased by hypoxia. Transfection of siRNA against HIFโ1ฮฑ abgrogated the hypoxic induction of cโMet, suggesting that cโMet expression is upregulated by a HIFโ1ฮฑโdependent mechanism. Hypoxia sensitized glioblastoma cell lines which showed hypoxic induction of cโMet to the motogenic effects of SF/HGF. These findings suggest that approximately half of all human glioblastomas respond to hypoxia with an induction of cโMet, which can enhance the stimulating effect of SF/HGF on tumor cell migration. ยฉ 2007 WileyโLiss, Inc.