Involvement of HIF1α in mediating VEGF-dependent epithelial cell growth and overexpression in chronic rhinosinusitis with nasal polyposis (91.4)

Abstract

Abstract We recently reported that VEGF is overexpressed in chronic rhinosinusitis (CRSwNP) and functions to promote nasal epithelial cell hyperplasia, a key feature of sinus polyposis, by regulating autocrine epithelial cell growth. However, the upstream signals regulating this process remain unclear. Hypoxia-inducible factor-1α (HIF1α) is a known regulator of VEGF. Therefore we examined whether HIF1α may regulate VEGF dependent cell growth in nasal epithelial cells. Immunohistochemical analysis of sinonasal surgical tissue showed significantly increased staining for HIF1α in epithelium in polyps of CRSwNP subjects as compared to normal control sinus tissue (p< 0.001, n=5). Culture of human primary nasal epithelial cells (PNEC) from CRSwNP subjects demonstrated abundant expression of HIF1α by realtime PCR (Ct=19+/-2, n=5). To implicate a role of HIF1α in regulation of VEGF in CRSwNP, we performed siRNA knockdown of HIF1α in PNEC from CRSwNP subjects. This resulted in specific inhibition of VEGF mRNA by 77% (p<0.01, n=3). ELISA of PNEC cell supernatants confirmed inhibition of soluble VEGF expression by 47% (p<0.01, n=3). In addition, silencing of HIF1α resulted in 56% reduction of cell growth rate comparable to that of PNECs from normal control subjects, as measured by DNA binding growth assay (p<0.01, n=3). These data suggest that HIF1α regulates VEGF in perpetuating hyperplastic epithelial cell growth observed in CRSwNP.