Gene expression analysis reveals evidence for inactivation of the TGF-β signaling cascade in autonomously functioning thyroid nodules

Abstract

Molecular eventsthat lead to the development of autonomously functioning thyroid nodules (AFTNs) are somatic mutations of the thyrotropin receptor (TSHR) in approximately 60% of the nodules and less frequently, somatic mutations in the G s a protein. However, AFTNs without known mutations indicate that other causes remain to be identified. Moreover, the impact of constitutively activating TSHR mutations on the signal transduction network of the thyroid epithelial cell is unknown. We therefore investigated gene expression in 15 AFTNs and their surrounding tissue using Affymetrix GeneChips. Most prominently, data analysis revealed a changed pattern of gene expression in the TGF-b signaling cascade and 25 differentially regulated genes in AFTNs, including thyroid peroxidase, type I iodothyronine deiodinase and sialyltransferase (SIAT) 1. Strikingly coexpression of SIAT 1 and TSHR in COS-7 cells increased TSH binding and cell surface expression of the TSHR. Moreover, differences in gene expression patterns for AFTNs with and without TSHR mutations indicate specific alterations of signal transduction in AFTNs without TSHR mutations. These results suggest that AFTNs with TSHR mutations harbor further mechanisms of forward stimulation. Furthermore, they give important leads to elucidate the molecular etiology of AFTNs without TSHR mutations.

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

“…First, where the two microarray analyses overlap, their results are similar, even though different samples and different arrays and protocols for samples processing were used. Second, we confirmed several regulations already identified previously (Deleu et al, 2000;Eszlinger et al, 2001Eszlinger et al, , 2004O'Donovan et al, 2002;Finley et al, 2004;Mazzanti et al, 2004;Detours et al, 2005). Moreover, several findings are in line with data obtained in different but related systems such as thyroid cells or other cells chronically stimulated by the cAMP pathway (Yamazaki et al, 2003).…”

“…Decreased expression of several genes confirms previous data obtained in our group and by others: ApoD, myosin (Eszlinger et al, 2004), c-fos, fosB, junB, c-myc and TR3 (NGFIB) (Deleu et al, 2000). Several genes are downregulated in both analysis I and II, but only by a factor of less than 3 in analysis II, namely clusterin, bcd, ATF3, cav1, DUSP1, junB and TR3.…”

“…Quite a few upregulations confirm previously obtained data: thyroperoxidase (Deleu et al, 2000), deiodinase (dio1), sialylyltransferase, protein kinase C b , collagen IV and IX (Eszlinger et al, 2004). FcGBP has been shown to be upregulated in follicular adenomas (O'Donovan et al, 2002).…”

“…While several groups have reported gene expression profiles in follicular adenomas and in follicular and papillary carcinomas (Huang et al, 2001;Aldred et al, 2003;Barden et al, 2003;Yano et al, 2004), only one similar study has been performed so far (Eszlinger et al, 2004). Our data set provides considerable new information about proteins and pathways involved in this disease, which will now be the subject of more detailed investigations.…”

“…FcGBP has been shown to be upregulated in follicular adenomas (O'Donovan et al, 2002). Alcohol DH (Eszlinger et al, 2004) and solute carrier expressions are also increased in the Tg-A2aR mice thyroids, an animal model of autonomous adenomas (Goffard et al, 2004). Phosphodiesterase expression is classically increased in response to cAMP and PKA activation (Cho-Chung, 2004).…”