Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a malignancy derived from the calcitonin-producing C-cells of the thyroid gland. Oncogenic mutations of the Ret proto-oncogene are found in all heritable

forms of MTC and roughly one half of the sporadic cases. However, several lines of evidence argue for the existence of additional genetic lesions necessary for the development of MTC.

Sprouty (Spry) family of genes is composed of four members in mammals (Spry1-4). Some Spry family members have been proposed as candidate tumor-suppressor genes in a variety of cancerous

pathologies. In this work, we show that targeted deletion of Spry1 causes C-cell hyperplasia, a precancerous lesion preceding MTC, in young adult mice. Expression of Spry1 restrains

proliferation of the MTC-derived cell line, TT. Finally, we found that the Spry1 promoter is frequently methylated in MTC and that Spry1 expression is consequently decreased. These findings

identify Spry1 as a candidate tumor-suppressor gene in MTC.

We are grateful to Esteban J Rozen for his initial contribution to the development of this work. We also thank Ana Velasco and Carme Guerris for technical assistance. This work was supported

by grants from Ministerio de Educación y Ciencia (BFU2007-67619 and BFU2010-17628) and Fundació La Marató de TV3, and funding from Suport als Grups de Recerca (2009 SGR 740) from

Generalitat de Catalunya to ME; grants 2009SGR794, RD06/0020/1034 and programa de intensificación de la investigación, Instituto Carlos III to XM-G; grants from Fondo de Investigaciones

Sanitarias (PI080883) and Fundación Mutua Madrileña (AP2775/2008) to MR; and from the Medical Research Council (G0601104) to MAB Tumor samples were obtained with the support of Xarxa

catalana de Bancs de Tumors, the Tumor Banc Platform of RTICC and RD09/0076/00059. AM is supported by a predoctoral fellowship from Universitat de Lleida and was supported by a fellowship

from a Fundació Alícia Cuello de Merigó. MV was recipient of a ‘beca d’introducció a la recerca’ fellowship from Universitat de Lleida.

Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida, Spain

Department of Pathology and Molecular Genetics, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida, Spain

Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

Department of Craniofacial Development, King's College London, London, UK

Supplementary Information accompanies the paper on the Oncogene website

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