Abstract A22: HIF-1 mediates up-regulation of urokinase-type activator receptor (uPAR) in cervical cancer cells

Abstract

Abstract A22 Hypoxia occurs during development of cervical cancer and is considered to correlate with its invasion. Hypoxia induces cancer cells to have more invasive property through the urokinase plasminogen activator receptor (uPAR) expression. We sought to determine the regulator(s) of uPAR expression during hypoxia. According to the invasion assays, cervical cancer cell lines, CaSki and CA, under hypoxic condotion (1% O2) showed more invasive property than those under normoxia. By western blot analysis, hypoxia enhanced the endogenous hypoxia inducible factor (HIF)-1alpha and uPAR protein expression. uPAR mRNA level was also up-regulated by hypoxia using realtime RT-PCR. Overexpression of HIF-1alpha which is induced by hypoxia activated the transcriptional activity of the uPAR promoter by luciferase assays. HIF-1 protein bound the putative HIF-1 response element on the uPAR promoter using the NoShift Transcription Factor Assay kit, and additional luciferase assays show that this is essential for uPAR transactivation by HIF-1. HIF-1 overexpression enhanced the endogenous uPAR expression and introduction of siRNA for HIF-1alpha diminishes uPAR expression during hypoxia. These results indicate the up-regulation of uPAR by hypoxia in cervical cancer cells is mediated through HIF-1. Using cervical cancer cell tissues, we also demonstrated that the level of uPAR mRNA in normal cervix is significantly lower than cervical cancer. Our results provide evidence that regulation of uPAR expression by HIF-1 represents a mechanism for cervical cancer invasion during hypoxia. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A22.