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Notch Signaling Is Involved in Expression of Thyrocyte Differentiation Markers and Is Down-Regulated in Thyroid Tumors

Dipartimento di Medicina Sperimentale (E.F., A.P., M.S.E., I.S., A.G.) and Scienze Cliniche (E.T., A.S., R.M., C.D., S.F.) and Istituto Pasteur (I.S., A.G.), Fondazione Cenci-Bolognetti, University of Rome La Sapienza, 00161 Rome, Italy; Neuromed Institute (A.G.), 86077 Pozzilli (Isernia), Italy; Dipartimento di Scienze Farmacobiologiche (D.R.), University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; and Department of Nuclear Medicine and Endocrine Oncology (M.S.), Institut Gustave Roussy and University Paris-Sud 11, 94805 Villejuif Cedex, France

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., 2a Clinica Medica, Dipartimento di Scienze Cliniche, Università degli Studi di Roma La Sapienza, V.le del Policlinico, 155, 00161 Rome, Italy. E-mail: sebastiano.filetti{at}uniroma1.it; or Alberto Gulino, Dipartimento di Medicina Sperimentale, Istituto Pasteur, Fondazione Cenci-Bolognetti, Università degli Studi di Roma La Sapienza, V.le del Policlinico, 155, 00161 Rome, Italy. E-mail: alberto.gulino{at}uniroma1.it.

Context: Notch genes encode receptors for a signaling pathway that regulates cell growth and differentiation in various contexts, but the role of Notch signaling in thyroid follicular cells has never been fully published.

Objective: The objective of the study was to characterize the expression of Notch pathway components in thyroid follicular cells and Notch signaling activities in normal and transformed thyrocytes.

Design/Setting and Patients: Expression of Notch pathway components and key markers of thyrocyte differentiation was analyzed in murine and human thyroid tissues (normal and tumoral) by quantitative RT-PCR and immunohistochemistry. The effects of Notch overexpression in human thyroid cancer cells and FTRL-5 cells were explored with analysis of gene expression, proliferation assays, and experiments involving transfection of a luciferase reporter construct containing human NIS promoter regions.

Results: Notch receptors are expressed during the development of murine thyrocytes, and their expression levels parallel those of thyroid differentiation markers. Notch signaling characterized also normal adult thyrocytes and is regulated by TSH. Notch pathway components are variably expressed in human normal thyroid tissue and thyroid tumors, but expression levels are clearly reduced in undifferentiated tumors. Overexpression of Notch-1 in thyroid cancer cells restores differentiation, reduces cell growth rates, and stimulates NIS expression via a direct action on the NIS promoter.

Conclusion: Notch signaling is involved in the determination of thyroid cell fate and is a direct regulator of thyroid-specific gene expression. Its deregulation may contribute to the loss of differentiation associated with thyroid tumorigenesis.