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

ABSTRACT: 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.

SUBMITTER: Miro C

PROVIDER: S-EPMC6881453 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Miro Caterina C Di Cicco Emery E Ambrosio Raffaele R Mancino Giuseppina G Di Girolamo Daniela D Cicatiello Annunziata Gaetana AG Sagliocchi Serena S Nappi Annarita A De Stefano Maria Angela MA Luongo Cristina C Antonini Dario D Visconte Feliciano F Varricchio Silvia S Ilardi Gennaro G Del Vecchio Luigi L Staibano Stefania S Boelen Anita A Blanpain Cedric C Missero Caterina C Salvatore Domenico D Dentice Monica M

Nature communications 20191127 1

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 increase ...[more]

PMID: 31776338

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Project description:BackgroundZinc-finger E-box binding homeobox 1 (ZEB-1), a member of the ZFH family, plays a key role in epithelial-mesenchymal transition during tumor progression in various cancers. However, little information is available on ZEB-1 expression in oral cavity squamous cell carcinoma (OSCC).MethodsThe expression levels of ZEB-1 and E-cadherin were assessed by immunohistochemistry in a cohort of 120 patients with OSCC treated by curative operation, and then the correlations between ZEB-1 and E-cadherin expression and clinical factors were evaluated, including patient prognosis. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to assess mRNA levels of ZEB-1 and E-cadherin in 20 matched OSCC specimens.ResultsPatients were followed up for a median period of 66 months (range 8-116 months), and 5-year overall survival was 68.3%. Positive ZEB-1 and E-cadherin immunostaining reactivity was detected in 64 (53.3%) and 53 (44.2%) patients, respectively. There was a negative correlation between ZEB-1 expression and E-cadherin expression. In addition, overexpression of ZEB-1 was significantly associated with recurrence, lymph node metastasis, and pathologic grading of patients, loss of E-cadherin was significantly associated with lymph node metastasis and pathologic grading of patients. Univariate analysis showed that increased ZEB-1 expression, loss of E-cadherin expression, lymph node metastasis, recurrence, and pathology grade were prognostic factors. In multivariate analysis, increased ZEB-1 expression and recurrence remained independent prognostic factors. In particular, patients with both ZEB-1 positivity and loss of E-cadherin expression had a poorer prognosis. qRT-PCR showed that ZEB-1 mRNA expression was higher in OSCC compared to the adjacent nontumorous tissues, while E-cadherin mRNA expression was lower in tumor tissues.ConclusionThis study shows that overexpression of ZEB-1 and loss of E-cadherin expression are significantly correlated with poor survival in OSCC patients, and ZEB-1 expression might serve as an independent prognostic biomarker of OSCC.

Dataset Information

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

Publications

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

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