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Epithelial-mesenchymal transition downregulates laminin α5 chain and upregulates laminin α4 chain in oral squamous carcinoma cells

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Abstract

Basement membranes maintain the epithelial phenotype and prevent invasion and metastasis. We hypothesized that expression of basement membrane laminins might be regulated by epithelial-mesenchymal transition (EMT), hallmark of cancer progression. As EMT is mediated by transcription factor Snail, we used oral squamous carcinoma cells obtained from a primary tumor (43A), from its EMT-experienced recurrence (43B) and Snail-transfected 43A cells (43A-SNA) displaying full EMT, as a model to study laminins and their receptors. Northern blotting, immunofluorescence, and immunoprecipitation showed a gradual loss of laminin-511 and its receptor Lutheran from 43A to 43B and 43A-SNA cells. In contrast, neoexpression of laminin α4 mRNA was found congruent with synthesis of laminin-411. Chromatin immunoprecipitation disclosed direct binding of Snail to regions upstream of laminin α5 and α4 genes. Immunofluorescence and immunoprecipitation showed a switch from hemidesmosomal integrin α6β4 to α6β1 and neoexpression of α1β1 in 43A-SNA cells, and upregulation of integrin-linked kinase in both 43B and 43A-SNA cells. The cells adhered potently to laminin-511 and fibronectin, whereas adhesion to laminin-411 was minimal. In contrast, laminin-411 inhibited cell adhesion to other extracellular matrix proteins. In conclusion, EMT induces a switch from laminin-511 to laminin-411 expression, which may be directly controlled by Snail. Concomitant changes take place in laminin- and collagen-binding receptors. Laminin-411 reduces adhesion to laminin-511 and fibronectin, suggesting that tumor cells could utilize laminin-411 in their invasive behavior.

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Abbreviations

BM:

Basement membrane

ECM:

Extracellular matrix

EMT:

Epithelial-mesenchymal transition

GAPDH:

Glutaraldehyde-3-phosphate-dehydrogenase

ILK:

Integrin-linked kinase

Lm:

Laminin

MAb:

Monoclonal antibody

Lu:

Lutheran

SCC:

Squamous cell carcinoma

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Acknowledgments

Professors J.H. Miner and V. Quaranta are acknowledged for providing valuable antibodies. The skillful technical assistance of Mika Hukkanen, Pipsa Kaipainen, Hannu Kamppinen, Reijo Karppinen, Marja-Leena Piironen, Outi Rauanheimo, Anne Reijula, and Hanna Wennäkoski is warmly appreciated. M.T. was supported by the K. Albin Johansson Stiftelse and the Suomalais-Norjalainen Lääketieteen Säätiö, M.A. and Y.T.K. by the Academy of Finland, the Biomedicum Helsinki Foundation, the Finska Läkaresällskapet, and the Helsinki University Central Hospital (EVO Grant), M.P. by the Swedish Cancer Society and the Karolinska Institute, and I.V. by the Helsinki University Central Hospital (EVO Grant no. TYH6269) and the Diabetes Research Foundation.

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Authors and Affiliations

  1. Institute of Biomedicine/Anatomy, University of Helsinki, P·O. Box 63 (Haartmaninkatu 8), 00014, Helsinki, Finland

    Minna Takkunen, Noora Vainionpää & Ismo Virtanen

  2. Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

    Mari Ainola & Yrjö T. Konttinen

  3. Department of Otorhinolaryngology, Head and Neck Surgery, Turku University Central Hospital, 20520, Turku, Finland

    Reidar Grenman

  4. Department of Odontology, Karolinska Institute, 141 04, Stockholm, Sweden

    Manuel Patarroyo

  5. Programa de Recerca en Càncer, IMIM-Hospital del Mar, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona (desp 298.03), c/Doctor Aiguader 88, 08003, Barcelona, Spain

    Antonio García de Herreros

  6. ORTON Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland

    Yrjö T. Konttinen

  7. COXA Hospital for Joint Replacement, Tampere, Finland

    Yrjö T. Konttinen

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  1. Minna Takkunen
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  2. Mari Ainola
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  8. Ismo Virtanen
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Correspondence to Minna Takkunen.

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Takkunen, M., Ainola, M., Vainionpää, N. et al. Epithelial-mesenchymal transition downregulates laminin α5 chain and upregulates laminin α4 chain in oral squamous carcinoma cells. Histochem Cell Biol 130, 509–525 (2008). https://doi.org/10.1007/s00418-008-0443-6

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