Gene expression analysis suggests a relevance of aberrant phosphatidylinositol-3-kinase signaling in cold thyroid nodules

Abstract

In contrast to autonomously functioning thyroid nodules the molecular cause of cold thyroid nodules, their benign, functionally inactive counterparts is so far largely unknown. Because of the partially dedifferentiated phenotype of cold thyroid nodules alterations in signaling cascades that favor proliferation but not differentiation are likely candidates for tumor induction and progression. The importance of Ras mutations for nodular development is still in question. Therefore, we investigated differentially expressed genes with respect to signaling cascades and aberrant signaling in 14 cold thyroid nodules and their normal surrounding tissue using Affymetrix GeneChips. Most prominently, data analysis revealed a reduced expression of Ras-MAPK cascade components (R-Ras, A-Raf, erk 1, mbp) and the PDGF receptor alpha, increased expression of phosphatidylinositol-3-kinase (PI-3-K) signaling molecules (p85 PI-3-K, p90 ribosomal protein S6 kinase alpha 2) and RasGAP 1 as well as increased expression of cell cycle associated genes. Moreover, we found 40 differentially regulated genes in cold thyroid nodules including several histone mRNAs. The increased expression of these histone mRNAs and of cyclin D1, cyclin H/cyclin dependent kinase 7 and cyclin B explains recent findings showing an increased proliferation in cold thyroid nodules compared to surrounding tissue or hot thyroid nodules (1). Furthermore, the decreased expression of Ras-MAPK cascade associated genes argues for a minor role of this cascade in CTNs. Whereas the increased expression of PI-3-K and ribosomal protein S6 kinase alpha 2 draws attention to the PI-3-K pathway which was not in focus for the development of CTNs so far. Therefore, further experiments have to evaluate the functional relevance of these findings.