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Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes

Oncogene volume 23, pages 3317–3327 (2004)Cite this article

Abstract

STAT3 is frequently overexpressed and constitutively activated by tyrosine phosphorylation during malignant transformation. Despite the clear importance of STAT3 in cell proliferation and survival in diverse human cancers, its possible contribution to tumor cell adhesion, motility and invasion remains hypothetical. We therefore compared the transforming properties of STAT3wt, its constitutively activated dimeric form STAT3C, and the dominant negative mutant STAT3-Y705F in human colorectal HCT8/S11 cancer cells. Both STAT3wt and STAT3C exert a permissive action to the proinvasive activity of the scatter factor HGF in HCT8/S11 cells. In contrast, the monomeric and cytoplasmic mutant Y705F induces a constitutive invasive phenotype through Wnt/Rho-independent and EGFR/PI3-kinase-dependent pathways. Accordingly, Y705F decreases cell–cell homotypic adhesions, and increases cell motility and scattering, as well as lamellipodia-type cellular extensions. STAT3-Y705F-transfected HCT8/S11 cells display an increased tyrosine phosphorylation of the cell–cell adhesion regulator β-catenin and its dissociation from the invasion suppressor E-cadherin at cell–cell contacts. Our data imply that both invasion promoter and repressor genes are controlled by the canonical STAT3 transcription pathways. Disruption of this cascade by Y705F reveals the proinvasive potential of altered forms of STAT3 as a persistent signaling adaptor in cytokine/transforming growth factor receptor scaffolds and oncogenic pathways.

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Acknowledgements

We are grateful to Drs S Roche, I Dusanter, L Pfeffer, J Darnell, L Debussche, LM Matrisian, P Polakis, C Caron, G Flatau and P Comoglio for providing reagents. This work was supported by INSERM, a post-doctoral fellowship from AstraZeneca (to SA), Research Grants from the Association de la Recherche sur le Cancer (ARC), the Groupement des Entreprises Françaises dans la Lutte Contre le Cancer France (to SA and CG), the Belgische Federatie tegen Kanker, the FORTIS Verzekeringen and the Fund for Scientific Research Flanders (Brussels, Belgium). CR is a PhD student supported by the French Ministry of the Scientific Research.

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  1. Christine Rivat and Olivier De Wever: These two authors contributed equally.

Authors and Affiliations

  1. INSERM U 482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, Paris, Cedex 12, 75571, France

    Christine Rivat, Christian Gespach & Samir Attoub

  2. Laboratory of Experimental Cancerology, University Hospital, De Pintelaan 185, Gent, B-9000, Belgium

    Olivier De Wever, Erik Bruyneel & Marc Mareel

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Correspondence to Samir Attoub.

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Rivat, C., Wever, O., Bruyneel, E. et al. Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes. Oncogene 23, 3317–3327 (2004). https://doi.org/10.1038/sj.onc.1207437

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