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Proteomic Profiling of Cold Thyroid Nodules

Medical Department III (K.K., S.K., D.F.), University of Leipzig, D-04103 Leipzig, Germany; Research Unit Enzymology of Protein Folding (A.S.), Max-Planck Society, D-06120 Halle/Saale, Germany; and Department of Histology (S.P., M.-C.M.), Universite Catholique de Louvain Medical School, B-1070 Brussels, Belgium

Address all correspondence and requests for reprints to: Dagmar Fuhrer M.D., Ph.D., Medizinische Klinik III, Universität Leipzig, Ph.-Rosenthal-Strasse 27, D-04103 Leipzig. E-mail: fued{at}medizin.uni-leipzig.de.

Cold thyroid nodules (CTNs) represent a frequent endocrine disorder accounting for up to 85% of thyroid nodules in a population living in an iodine-deficient area. Benign CTNs need to be distinguished from thyroid cancer, which is relatively rare. The molecular etiology of benign CTNs is unresolved. To obtain novel insights into their pathogenesis, protein expression profiling was performed in a series of 27 solitary CTNs (10 follicular adenoma and 20 adenomatous nodules) and surrounding normal thyroid tissues using two-dimensional gel electrophoresis combined with mass spectrometry analysis, Western blotting, and immunohistochemistry. The proteome analysis revealed a specific fingerprint of CTNs with up-regulation of three functional systems: 1) thyroid cell proliferation, 2) turnover of thyroglobulin, and 3) H₂O₂ detoxification. Western blot analysis and immunohistochemistry confirmed the proteome data and showed that CTNs exhibit significant up-regulation of proteins involved in thyroid hormone synthesis yet are deficient in T₄-containing thyroglobulin. This is consequential to intranodular iodide deficiency, mainly due to cytoplasmic sodium iodide symporter localization, and portrays the CTN as an activated proliferating lesion with an intranodular hypothyroid milieu. Furthermore, we provide preliminary evidence that up-regulation of H₂O₂ generation in CTNs could override the antioxidative system resulting in oxidative stress, which is suggested by the finding of raised 8-oxo-guanidine DNA adduct formation in CTNs.