Thyroid hormone induces progression and invasiveness of squamous cell carcinomas by promoting a ZEB-1/E-cadherin switch

Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mese...

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Bibliographic Details
Published in:	Nature communications 2019-11, Vol.10 (1), p.5410-5410, Article 5410
Main Authors:	Miro, Caterina, Di Cicco, Emery, Ambrosio, Raffaele, Mancino, Giuseppina, Di Girolamo, Daniela, Cicatiello, Annunziata Gaetana, Sagliocchi, Serena, Nappi, Annarita, De Stefano, Maria Angela, Luongo, Cristina, Antonini, Dario, Visconte, Feliciano, Varricchio, Silvia, Ilardi, Gennaro, Del Vecchio, Luigi, Staibano, Stefania, Boelen, Anita, Blanpain, Cedric, Missero, Caterina, Salvatore, Domenico, Dentice, Monica
Format:	Article
Language:	eng
Subjects:	Adult Aged Aged, 80 and over Animals Antigens, CD - metabolism Cadherins - metabolism Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Cell Line, Tumor Cell Movement Deactivation E-cadherin Enzymes Epithelial-Mesenchymal Transition Gene expression Humans Inactivation Intracellular levels Invasiveness Iodide Peroxidase - genetics Iodide Peroxidase - metabolism Iodothyronine Deiodinase Type II Mesenchyme Metastases Metastasis Mice, Transgenic Middle Aged Skin Neoplasms - genetics Skin Neoplasms - metabolism Skin Neoplasms - pathology Squamous cell carcinoma Thyroid Thyroid gland Thyroid Hormones - metabolism Transcription Triiodothyronine Tumors Zinc Finger E-box-Binding Homeobox 1 - genetics Zinc Finger E-box-Binding Homeobox 1 - metabolism
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Summary:	Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mesenchymal genes and metalloproteases and suppresses E-cadherin expression. Accordingly, in human SCC, elevated D2 (the T3-producing enzyme) correlates with tumor grade and is associated with an increased risk of postsurgical relapse and shorter disease-free survival. These data provide the first in vivo demonstration that TH and its activating enzyme, D2, play an effective role not only in the EMT but also in the entire neoplastic cascade starting from tumor formation up to metastatic transformation, and supports the concept that TH is an EMT promoter. Our studies indicate that tumor progression relies on precise T3 availability, suggesting that pharmacological inactivation of D2 and TH signaling may suppress the metastatic proclivity of SCC.
ISSN:	2041-1723 2041-1723