[Proc Amer Assoc Cancer Res, Volume 45, 2004]
Cellular, Molecular, and Tumor Biology 67: Gene Regulation and Tumor Invasion
Furin inhibition blocked hypoxia-induced invasion of fibrosarcoma cells. Involvement of HIF-1-induced furin gene expression.
Claire M. Dubois,
Sebastien Grandmont and
University of Sherbrooke, Sherbrooke, PQ, Canada
Hypoxia has been recently shown to regulate the in vitro invasion of cancer cells, through the stabilization of the hypoxia-inducible transcription factor HIF-1. Important properties of invasive cancer cells include decreased cell-cell adhesion and increased in ECM remodeling. These events are under the control of key mediators known to be activated by the proprotein convertase furin such as the metalloproteinase MT1-MMP, the integrin E-cadherin and the growth factor TGFbeta. To gain further insights into the mechanism by which hypoxia regulates cell invasion, we tested the impact of furin inhibition on the in vitro invasion of the HT-1080 fibrosarcoma cell line. Stable transfectants were generated using a pcDNA3 vector encoding the furin inhibitor alpha1-PDX or an empty control vector. In control cells, hypoxia (1% O2, 24 h) strongly increased cell invasiveness, an event that correlated with the induction of furin gene expression. Furin inhibition throught alpha1-PDX overexpression, blocked the increased invasiveness of HT-1080 cells due to low oxygen exposition. In luciferase assays, overexpression of the HIF-1 alpha subunit resulted in a marked increased in furin promoter activity, whereas transfection of a dominant negative form of HIF-1alpha impaired hypoxia-induced activity. Similarly, furin promoter activity was increased in the parental Hepa c1c7 cell line but not in the HIF1beta/ARNT-deficient Hepa c4 cells. Together, these results clearly demonstrate the requirement for HIF-1 in the hypoxic regulation of the furin gene and provide additional insights into the mechanism by which hypoxia increases cell invasion.
Copyright © 2004 by the American Association for Cancer Research.