Hif-1\#945; Mediates Hypoxia Modulation Of Ews-Fli1 Expression In Ewing\#8217;S Sarcoma Family Tumors

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO\n\nHypoxia is an important phenomenon in the tumor cell microenvironment. Tumor hypoxia is associated with a more aggressive phenotype due to the induction of a number of genes, the majority of which are regulated by hypoxia-inducible factor-1 (HIF-1). The Ewing\\#8217;s sarcoma family tumors (ESFT) are highly malignant bone-associated pediatric cancers that are defined by virtually a single oncogenic aberration, the EWS-FLI1 gene fusion. Considering the important role low oxygen plays in the microenvironment of solid tumors, we investigated the role of hypoxia in ESFT cells in vitro. We found that EWS-FLI1 protein and mRNA expression are up-regulated by hypoxia in a HIF-1\\#945;-dependent manner. Microarray analysis pointed to a subset of genes being dependent on EWS-FLI1 for hypoxic modulation. Knocking down HIF-1\\#945; with a specific short hairpin RNA under hypoxia resulted in suppression of EWS-FLI1 protein and mRNA expression. Conversely, expressing a non-degradable HIF-1\\#945; mutant construct under normoxia resulted in EWS-FLI1 expression enhancement. By treating cells under hypoxia with several different kinase inhibitors, we also show that NF\\#954;B and PI3K pathways may play a role in HIF-1\\#945;-mediated EWS-FLI1 expression enhancement under hypoxia. Our data identify HIF-1\\#945; and hypoxia as important factors in the regulation of the pathognomonic Ewing´s sarcoma oncogene EWS-FLI1, and this may have far-reaching consequences for the course of the disease.\n\nCitation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 247.