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Transcriptional activation of interleukin-8 by beta-catenin-Tcf4
Laurence Lévy1, Christine Neuveut, Claire-Angélique Renard
1Unité de Recombinaison et Expression Génétique (Inserm U163), Département de Médecine Moléculaire, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France.
Abstract:
Nuclear translocation of beta-catenin and its association with Tcf/Lef factors are key steps in transduction of the Wnt signal, which is aberrantly activated in a variety of human cancers. In a search for new beta-catenin-Tcf target genes, we analyzed beta-catenin-induced alterations of gene expression in primary human hepatocytes, after transduction of either dominant stable beta-catenin or its truncated, transactivation-deficient counterpart by means of a lentiviral vector. cDNA microarray analysis revealed a limited set of up-regulated genes, including known Wnt targets such as matrilysin and keratin-1. In this screen, we identified the CXC chemokine interleukin 8 (IL-8) as a direct target of beta-catenin-Tcf4. IL-8 is constitutively expressed in various cancers, and it has been implicated in tumor progression through its mitogenic, motogenic, and angiogenic activities. The IL-8 promoter contains a unique consensus Tcf/Lef site that is critical for IL-8 activation by beta-catenin. We show here that the p300 coactivator was required for efficient transactivation of beta-catenin on this promoter. Ectopic expression of beta-catenin in hepatoma cells promoted IL-8 secretion, which stimulated endothelial cell migration. These data define IL-8 as a Wnt target and suggest that IL-8 induction by beta-catenin might be implicated in developmental and tumorigenic processes.
Insights
Researchers identified Interleukin-8 (IL-8) as a direct target of beta-catenin signaling. This Wnt pathway activation promotes IL-8 expression, potentially driving cancer development and progression.
Area of Science:
- Molecular Biology
- Oncology
- Cell Signaling
Background:
- Aberrant Wnt signaling, involving beta-catenin and Tcf/Lef factors, is crucial in human cancers.
- Identifying novel Wnt target genes is essential for understanding cancer pathogenesis.
Purpose of the Study:
- To identify new beta-catenin-Tcf target genes using gene expression analysis.
- To investigate the role of Interleukin-8 (IL-8) in Wnt pathway activation and cancer.
Main Methods:
- Primary human hepatocytes were transduced with lentiviral vectors expressing beta-catenin variants.
- cDNA microarray analysis was employed to assess gene expression changes.
- Reporter assays and coactivator studies were performed to validate IL-8 as a target.
Main Results:
- Interleukin-8 (IL-8) was identified as a direct target gene induced by beta-catenin-Tcf4.
- A unique Tcf/Lef binding site in the IL-8 promoter was critical for beta-catenin-mediated activation.
- The p300 coactivator was required for beta-catenin transactivation of the IL-8 promoter.
- Ectopic beta-catenin expression increased IL-8 secretion, promoting endothelial cell migration.
Conclusions:
- IL-8 is a novel Wnt target gene regulated by beta-catenin and Tcf4.
- Beta-catenin-induced IL-8 expression may contribute to tumor development and progression through its angiogenic and motogenic activities.