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doi: 10.1242/10.1242/jcs.00091

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Transforming growth factor-ß and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes

¹ Institute of Anatomy and Cell Biology, Göteborg University, Göteborg, Sweden
² Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University Hospital, Uppsala, Sweden

^* Author for correspondence (e-mail: mats.grande{at}anatcell.gu.se)

Accepted 7 August 2002

Enhancement of tumor cell growth and invasiveness by transforming growth factor-ß (TGF-ß) requires constitutive activation of the ras/MAPK pathway. Here we have investigated how MEK activation by epidermal growth factor (EGF) influences the response of fully differentiated and growth-arrested pig thyroid epithelial cells in primary culture to TGF-ß1. The epithelial tightness was maintained after single stimulation with EGF or TGF-ß1 (both 10 ng/ml) for 48 hours. In contrast, co-stimulation abolished the transepithelial resistance and increased the paracellular flux of [³H]inulin within 24 hours. Reduced levels of the tight junction proteins claudin-1 and occludin accompanied the loss of barrier function. N-cadherin, expressed only in few cells of untreated or single-stimulated cultures, was at the same time increased 30-fold and co-localised with E-cadherin at adherens junctions in all cells. After 48 hours of co-stimulation, both E- and N-cadherin were downregulated and the cells attained a fibroblast-like morphology and formed multilayers. TGF-ß1 only partially inhibited EGF-induced Erk phosphorylation. The MEK inhibitor U0126 prevented residual Erk phosphorylation and abrogated the synergistic responses to TGF-ß1 and EGF. The observations indicate that concomitant growth factor-induced MEK activation is necessary for TGF-ß1 to convert normal thyroid epithelial cells to a mesenchymal phenotype.

Key words: Claudin, E-cadherin, EGF, EMT, Erk, N-cadherin, Occludin, TGF-ß, Thyroid

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