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Gene Expression Analysis Reveals Evidence for Increased Expression of Cell Cycle-Associated Genes and G_q-Protein-Protein Kinase C Signaling in Cold Thyroid Nodules

III. Medical Department (M.E., K.K., K.B., D.F., R.P.), and Interdisciplinary Center for Clinical Research Leipzig (K.K.), University of Leipzig, D-04103 Leipzig, Germany; Institute of Biometrics and Medical Informatics (J.L., S.K.), University of Magdeburg, D-39120 Magdeburg, Germany; and Interdisciplinary Center for Bioinformatics Leipzig (M.B.), University of Leipzig, D-04107 Leipzig, Germany

Address all correspondence and requests for reprints to: R. Paschke, M.D., III. Medical Department, University of Leipzig, Philipp-Rosenthal-Strasse 27, D-04103 Leipzig, Germany. E-mail: pasr{at}medizin.uni-leipzig.de.

In contrast to the molecular etiology of autonomously functioning thyroid nodules, the molecular cause of cold thyroid nodules (CTNs), their benign, functional inactive counterparts, are so far largely unknown. Because of the partially dedifferentiated phenotype of CTNs, alterations in signaling cascades that favor proliferation, but not differentiation, are likely candidates for tumor induction and progression. The importance of RAS mutations for the development of benign nodules with follicular histology is still in question. However, differentially expressed genes in the context of their signaling cascades could define aberrant signaling in CTNs. Therefore, we investigated gene expression in 22 CTNs and their normal surrounding tissue using Affymetrix GeneChips. Most prominently, data analysis revealed an increased expression of cell cycle-associated genes and a special relevance of protein kinase C signaling, whereas no evidence of RAS-MAPK signaling in CTNs was found. Moreover, we determined 31 differentially regulated genes in CTNs, including several histone mRNAs. Taken together, these results explain recent findings showing an increased proliferation in CTNs and draw attention to protein kinase C signaling, but away from RAS-MAPK signaling, as being involved in the etiology of CTNs.

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