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Testori J.,Medical University of Vienna | Schweighofer B.,Medical University of Vienna | Schweighofer B.,Scripps Research Institute | Helfrich I.,German Cancer Research Center | And 11 more authors.
Blood | Year: 2011

The HLX gene encoding a diverged homeobox transcription factor has been found to be up-regulated by vascular endothelial growth factor-A (VEGF-A) in endothelial cells. We have now investigated the gene repertoire induced by HLX and its potential biologic function. HLX strongly increased the transcripts for several repulsive cell-guidance proteins including UNC5B, plexin-A1, and semaphorin-3G. In addition, genes for transcriptional repressors such as HES-1 were up-regulated. In line with these findings, adenoviral overexpression of HLX inhibited endothelial cell migration, sprouting, and vessel formation in vitro and in vivo, whereas proliferation was unaffected. This inhibition of sprouting was caused to a significant part by HLXmediated up-regulation of UNC5B as shown by short hairpin RNA (shRNA)-mediated down-modulation of the respective mRNA. VEGF-A stimulation of endothelial cells induced elevated levels of HLX over longer time periods resulting in especially high up-regulation of UNC5B mRNA as well as an increase in cells displaying UNC5B at their surface. However, induction of HLX was strongly reduced and UNC5B up-regulation completely abrogated when cells were exposed to hypoxic conditions. These data suggest that HLX may function to balance attractive with repulsive vessel guidance by up-regulating UNC5B and to downmodulate sprouting under normoxic conditions. © 2011 by The American Society of Hematology.

Hudelist G.,Medical University of Vienna | Hudelist G.,Vienna University Hospital | Huber A.,Medical University of Vienna | Auer M.,Ludwig Boltzmann Institute for Clinical and Experimental Oncology | And 10 more authors.
Reproductive BioMedicine Online | Year: 2010

Preliminary studies have shown that systemic β-human chorionic gonadotropin (βHCG) therapy alleviates endometriosis-related chronic pelvic pain. The underlying mechanism, however, is completely unknown. This study has investigated the dose-dependent alterations in the overall gene expression profile of endometriosis-derived stromal cells under increasing concentrations of βHCG by using the Affymetrix GeneChip U133 Set. It has been previously shown that βHCG concentrations of 0.1 U/ml and higher lead to a significant and dose-dependent increase in the expression of 68 genes. This study reports on a cluster analysis which identified three clusters of genes with a comparable expression pattern in response to increasing concentrations of βHCG. Most of the up-regulated genes encoded proteins that are involved in cell adhesion, intercellular communication, extracellular matrix remodelling, apoptosis and inflammation. Stromal monocultures from eight patients, treated with and without 50 U/ml of βHCG, were then incubated and real-time polymerase chain reaction for the highly up-regulated genes PAI2, DUSP6, PLAU and MMP1 performed in order to validate the cDNA array findings in patients with endometriosis. Taken together, this study shows that βHCG induces dose-dependent characteristic response clusters in the gene expression profile of stromal cells obtained from endometriotic lesions which could explain the differential biological responses of βHCG in endometriosis. © 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

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