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Similar NF-[kappa]B Gene Signatures in TNF-[alpha] Treated Human Endothelial Cells and Breast Tumor Biopsies

Endothelial dysfunction has been implicated in the pathogenesis of diverse pathologies ranging from vascular and immune diseases to cancer. TNF-[alpha] is one of the mediators of endothelial dysfunction through the activation of transcription factors, including NF-[kappa]B. While HUVEC (macrovascula...

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Bibliographic Details
Published in:PloS one 2011-07, Vol.6 (7), p.e21589
Main Authors: Perrot-Applanat, Martine, Vacher, Sophie, Toullec, Aurore, Pelaez, Irma, Velasco, Guillaume, Cormier, Françoise, Saad, Hanan El Sheikh, Lidereau, Rosette, Baud, Véronique, Bièche, Ivan
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Language:English
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Summary:Endothelial dysfunction has been implicated in the pathogenesis of diverse pathologies ranging from vascular and immune diseases to cancer. TNF-[alpha] is one of the mediators of endothelial dysfunction through the activation of transcription factors, including NF-[kappa]B. While HUVEC (macrovascular cells) have been largely used in the past, here, we documented an NF-[kappa]B gene signature in TNF[alpha]-stimulated microvascular endothelial cells HMEC often used in tumor angiogenesis studies. We measured mRNA expression of 55 NF-[kappa]B related genes using quantitative RT-PCR in HUVEC and HMEC. Our study identified twenty genes markedly up-regulated in response to TNF[alpha], including adhesion molecules, cytokines, chemokines, and apoptosis regulators, some of them being identified as TNF-[alpha]-inducible genes for the first time in endothelial cells (two apoptosis regulators, TNFAIP3 and TNFRSF10B/Trail R2 (DR5), the chemokines GM-CSF/CSF2 and MCF/CSF1, and CD40 and TNF-[alpha] itself, as well as NF-[kappa]B components (RELB, NFKB1or 50/p105 and NFKB2 or p52/p100). For eight genes, the fold induction was much higher in HMEC, as compared to HUVEC. Most importantly, our study described for the first time a connection between NF-[kappa]B activation and the induction of most, if not all, of these genes in HMEC as evaluated by pharmacological inhibition and RelA expression knock-down by RNA interference. Taken together these data suggest the potential use of this NF-[kappa]B gene signature in analyzing the role of TNF-[alpha] in the endothelial dysfunction, as well as in breast tumors independently of the presence of ER[alpha].
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0021589