Hypoxia-inducible factor 1α (HIF-1α) regulates the transcription of a number of genes under
hypoxia and other extracellular stimulations. It has been shown that
E-cadherin is down-regulated by
epidermal growth factor receptor (
EGF) stimulation, and that cells with low
E-cadherin expression are more invasive. Our recent study demonstrated a novel mechanism by which
EGF down-regulates
E-cadherin expression through production of
hydrogen peroxide (H(2)O(2)) and the activation of
p38 MAPK in human
ovarian cancer cells. In this study, we were interested in examining the potential role of HIF-1α in cell invasion under normoxic conditions, specifically when cells are treated with
EGF, which is known to down-regulate
E-cadherin and increase invasiveness. We show that
EGF treatment induces HIF-1α expression in two human
ovarian cancer cell lines (SKOV3 and OVCAR5), and that this effect is diminished by treatment with a membrane-permeable H(2)O(2) scavenger,
PEG-catalase. However, the induction of HIF-1α by
EGF did not require the activation of
p38 MAPK. Treatment with
siRNA targeting HIF-1α reduces both basal and
EGF-induced HIF-1α levels. Importantly, treatment with HIF-1α
siRNA diminishes the up-regulation of Snail and Slug as well as the down-regulation of
E-cadherin by
EGF. The involvement of HIF-1α in the down-regulation of
E-cadherin was confirmed with
cobalt chloride (
CoCl(2)), a
hypoxia-mimetic
reagent. Finally, we also show that
EGF-induced cell invasion is attenuated by treatment with HIF-1α
siRNA. This study demonstrates an important role for HIF-1α in mediating the effects of
EGF on Snail, Slug and
E-cadherin expression as well as invasiveness in human
ovarian cancer cells.