Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail

Authors

  • Stefan Grotegut,

    1. Department of Clinical-Biological Sciences, Institute of Biochemistry and Genetics, Center of Biomedicine, University of Basel, Basel, Switzerland
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  • Dietrich von Schweinitz,

    1. Department of Pediatric Surgery, Ludwig-Maximilians University, Munich, Germany
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  • Gerhard Christofori,

    Corresponding author
    1. Department of Clinical-Biological Sciences, Institute of Biochemistry and Genetics, Center of Biomedicine, University of Basel, Basel, Switzerland
    • Corresponding author. Department of Clinical-Biological Sciences, Institute of Biochemistry and Genetics, Center of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Tel.: +41 61 267 3562; Fax: +41 61 267 3566; E-mail: Gerhard.Christofori@unibas.ch

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  • François Lehembre

    1. Department of Clinical-Biological Sciences, Institute of Biochemistry and Genetics, Center of Biomedicine, University of Basel, Basel, Switzerland
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Abstract

Hepatocyte growth factor/scatter factor (HGF) exerts several functions in physiological and pathological processes, among them the induction of epithelial cell scattering and motility. Its pivotal role in angiogenesis, tumor progression, and metastasis is evident; however, the underlying molecular mechanisms are still poorly understood. Here, we demonstrate that HGF induces scattering of epithelial cells by upregulating the expression of Snail, a transcriptional repressor involved in epithelial–mesenchymal transition (EMT). Snail is required for HGF-induced cell scattering, since shRNA-mediated ablation of Snail expression prevents this process. HGF-induced upregulation of Snail transcription involves activation of the mitogen-activated protein kinase (MAPK) pathway and requires the activity of early growth response factor-1 (Egr-1). Upon induction by Egr-1, Snail represses the expression of E-cadherin and claudin-3 genes. It also binds to the Egr-1 promoter and represses Egr-1 transcription, thereby establishing a negative regulatory feedback loop. These findings indicate that Snail upregulation by HGF is mediated via the MAPK/Egr-1 signaling pathway and that both Snail and Egr-1 play a critical role in HGF-induced cell scattering, migration, and invasion.

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