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First published online 22 January 2008
doi: 10.1242/jcs.017202

Journal of Cell Science 121, 477-486 (2008)
Published by The Company of Biologists 2008
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Research Article

ER stress is associated with dedifferentiation and an epithelial-to-mesenchymal transition-like phenotype in PC Cl3 thyroid cells

Luca Ulianich1, Corrado Garbi2, Antonella Sonia Treglia3, Dario Punzi2, Claudia Miele1, Gregory Alexander Raciti1,2, Francesco Beguinot1,2, Eduardo Consiglio1,2 and Bruno Di Jeso3,*

1 Istituto di Endocrinologia ed Oncologia Sperimentale "G. Salvatore", Via S. Pansini 5, 80131 Napoli, Italy
2 Dipartimento di Biologia e Patologia Cellulare e Molecolare `L. Califano', Via S. Pansini 5, 80131 Napoli, Italy
3 Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Facoltà di Scienze Matematiche Fisiche e Naturali, Università degli Studi di Lecce, Strada Provinciale Lecce-Monteroni, 73100 Lecce, Italy

* Author for correspondence (e-mail: bdijeso{at}ilenic.unile.it)

Accepted 15 November 2007

Conditions perturbing the homeostasis of the endoplasmic reticulum (ER) cause accumulation of unfolded proteins and trigger ER stress. In PC Cl3 thyroid cells, thapsigargin and tunicamycin interfered with the folding of thyroglobulin, causing accumulation of this very large secretory glycoprotein in the ER. Consequently, mRNAs encoding BiP and XBP-1 were induced and spliced, respectively. In the absence of apoptosis, differentiation of PC Cl3 cells was inhibited. mRNA and protein levels of the thyroid-specific genes encoding thyroglobulin, thyroperoxidase and the sodium/iodide symporter and of the genes encoding the thyroid transcription factors TTF-1, TTF-2 and Pax-8 were dramatically downregulated. These effects were, at least in part, transcriptional. Moreover, they were selective and temporally distinct from the general and transient PERK-dependent translational inhibition. Thyroid dedifferentiation was accompanied by changes in the organization of the polarized epithelial monolayer. Downregulation of the mRNA encoding E-cadherin, and upregulation of the mRNAs encoding vimentin, {alpha}-smooth muscle actin, {alpha}(1)(I) collagen and SNAI1/SIP1, together with formation of actin stress fibers and loss of trans-epithelial resistance were found, confirming an epithelial-mesenchymal transition (EMT). The thyroid-specific and epithelial dedifferentiation by thapsigargin or tunicamycin were completely prevented by the PP2 inhibitor of Src-family kinases and by stable expression of a dominant-negative Src. Together, these data indicate that ER stress induces dedifferentiation and an EMT-like phenotype in thyroid cells through a Src-mediated signaling pathway.

Key words: ER stress, Thyroid cells, Dedifferentiation, Epithelial-mesenchymal transition


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