Comparison of differential gene expression of hot and cold thyroid nodules with primary epithelial cell culture models by investigation of co-regulated gene sets

Both autonomously functioning thyroid nodules (AFTNs) and cold thyroid nodules (CTNs) are characterized by an increased proliferation, however, they have opposite functional activities. Therefore, with the aim to further understand the distinct molecular pathology of each entity and to discover common mechanisms like those leading to increased proliferation in both, AFTNs and CTNs, we now compared gene expression of AFTNs and CTNs with in vitro model systems (TSH-stimulated and ras-transfected primary cultures (PC)) whose gene expression patterns can be attributed to specific molecular alterations. Since combinations of co-regulated genes are more likely to reveal molecular mechanisms, we used a procedure which groups co-regulated genes within “gene sets”. We found a co-regulated gene set in the AFTNs that overlaps with differential expression in TSH-stimulated PCs but not in CTNs or ras-transfected PCs. In addition to thyroid peroxidase and sialyltransferase 1, this set of co-regulated genes comprises metallothioneins and the G-protein-coupled receptor 56. Although their role in the thyroid is unknown so far, their appearance in one group indicates a functional relevance in TSH–TSH receptor-stimulated mechanisms. Furthermore, we identified down-regulated gene sets with concordant expression patterns in AFTNs, CTNs and ras-transfected PCs. However, these expression patterns are not of relevance in the TSH-stimulated PCs. These findings suggest that TSH-stimulated PCs can be used as a model of increased thyroid function (AFTNs), whereas the ras-transfected PCs better reflect the increased proliferation of both AFTNs and CTNs.