Modulation of Thyroid-Specific Gene Expression in Normal and Nodular Human Thyroid Tissues from Adults: An in Vivo Effect of Thyrotropin

Bruno, Rocco; Ferretti, Elisabetta; Tosi, E; Arturi, Franco; Giannasio, P.; Mattei, Tiziana; Scipioni, Angela; Presta, Ivan; Morisi, R.; Gulino, Alberto; Filetti, Sébastiano; Russo, Diego

doi:10.1210/jc.2005-0800

Cited by 45 publications

(28 citation statements)

References 24 publications

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“…Furthermore, the highest reduction were those of NIS and TPO expression. NIS expression reduction without decrease of TPO expression levels in benign adenomas have been previously described (19)(20). Indeed, in the present study, the expression of NIS and TPO were 150 and 230-fold lower, respectively, in the nodule when compared with non-nodular or normal thyroid tissue.…”

Section: Discussionsupporting

confidence: 73%

A molecular analysis and long-term follow-up of two siblings with severe congenital hypothyroidism carrying the IVS30+1G>T intronic thyroglobulin mutation

Rubio

Galrão

Pardo

et al. 2008

Arq Bras Endocrinol Metab

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Objective: To extend the molecular analysis of the IVS30+1G>T intronic thyroglobulin (TG) mutation, and to report the eleven year follow-up of the affected patients. Methods: Two siblings with severe congenital hypothyroidism with fetal and neonatal goiter, harboring the IVS30+1G>T mutation were included. Nodular and non-nodular thyroid tissue specimens were collected. Specifi c thyroid genes expression was evaluated by real-timePCR and by immunohistochemistry. Results: In non-nodular tissue specifi c thyroid genes mRNA were reduced when compared to normal thyroid sample. In the nodule, TPO and NIS expression was very low. Microscopic examinations showed very large follicular-lumina and swollen vesicles of endoplasmatic-reticulum. Strong cytoplasmatic and low follicular-lumen TG immunostaining were detected. Intracellular NIS, membrane TPO and TSHR immunostaining had higher positivity in nonnodular sample. Both patients had a long-term adequate developmental outcome, besides one patient have been lately-treated. Conclusions: IVS30+1G>T mutation not only lead to very enlarge endoplasmatic-reticulum, but also to alterations of specifi c thyroid genes expression. The clinical evolution of patients harboring these mutations strengthen the concept of the infl uence of environment, like iodine nutrition, to determine the fi nal phenotypic appearance. RESUMO Análise Molecular e Acompanhamento a Longo Prazo de Dois Irmãos com Hipotireoidismo Congênito Portadores da Mutação Intrônica IVS30+1G>T noGene da Tireoglobulina. Objetivo: Aprofundar a análise molecular da mutação intrônica IVS30+1G>T do gene tireoglobulina (TG) e relatar a clínica de pacientes portadores da mutação, acompanhados por 11 anos. Métodos: Foram estudados dois irmãos com hipotireoidismo congênito grave com bócio fetal e bócio neonatal, portadores da mutação IVS30+1G>T. Foram coletadas amostras de tecido nodular e não-nodular. Avaliou-se a expressão de genes específi cos da tireóide por PCR em tempo real e imunohistoquímica. Resultados: A expressão de genes específi -cos da tireóide foi menor no tecido não-nodular que no tecido normal controle. Expressões de TPO e NIS foram extremamente baixas no tecido nodular. Verifi cou-se lúmen folicular aumentado com grandes vesículas de retículo endoplasmático, e detectou-se forte marcação de TG no citoplasma e fraca no lúmen folicular. No tecido não-nodular observou-se forte positividade de NIS intracelular e, TPO e TSHR na membrana plasmática. O acompanhamento em longo prazo dos pacientes mostrou adequado desenvolvimento, apesar de um deles ter recebido tratamento tardio. Conclusões: A mutação IVS30+1G>T não só promove alterações no retículo endoplasmático, como alterações na expressão de genes específi cos da tireóide. A evolução clínica destes pacientes reforça o conceito da infl uência do meio ambiente, como o aporte nutricional de iodo, no fenótipo fi nal.

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Section: Discussionsupporting

confidence: 73%

A molecular analysis and long-term follow-up of two siblings with severe congenital hypothyroidism carrying the IVS30+1G>T intronic thyroglobulin mutation

Rubio

Galrão

Pardo

et al. 2008

Arq Bras Endocrinol Metab

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“…Using an in vivo model of normal human thyroid cells, we previously demonstrated that TSH suppression affects NIS mRNA levels but not those of TSHR (Bruno et al 2005). Characterization of the elements that regulate TSHR (Kakinuma et al 1996) and NIS (Chiefari et al 2002) expression has stimulated/facilitated attempts to identify the roles these genes play in human thyroid cancer.…”

Section: Discussionmentioning

confidence: 99%

Different expression of TSH receptor and NIS genes in thyroid cancer: role of epigenetics

D’Agostino¹,

Sponziello²,

Puppin³

et al. 2013

Journal of Molecular Endocrinology

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The TSH receptor (TSHR) and sodium/iodide symporter (NIS) are key players in radioiodinebased treatment of differentiated thyroid cancers. While NIS (SLC5AS) expression is diminished/lost in most thyroid tumors, TSHR is usually preserved. To examine the mechanisms that regulate the expression of NIS and TSHR genes in thyroid tumor cells, we analyzed their expression after inhibition of ras-BRAF-MAPK and PI3K-Akt-mTOR pathways and the epigenetic control occurring at the gene promoter level in four human thyroid cancer cell lines. Quantitative real-time PCR was used to measure NIS and TSHR mRNA in thyroid cancer cell lines (TPC-1, BCPAP, WRO, and FTC-133). Western blotting was used to assess the levels of total and phosphorylated ERK and Akt. Chromatin immunoprecipitation was performed for investigating histone post-translational modifications of the TSHR and NIS genes. ERK and Akt inhibitors elicited different responses of the cells in terms of TSHR and NIS mRNA levels. Akt inhibition increased NIS transcript levels and reduced those of TSHR in FTC-133 cells but had no significant effects in BCPAP. ERK inhibition increased the expression of both genes in BCPAP cells but had no effects in FTC-133. Histone posttranslational modifications observed in the basal state of the four cell lines as well as in BCPAP treated with ERK inhibitor and FTC-133 treated with Akt inhibitor show cell-and gene-specific differences. In conclusion, our data indicate that in thyroid cancer cells the expression of TSHR and NIS genes is differently controlled by multiple mechanisms, including epigenetic events elicited by major signaling pathways involved in thyroid tumorigenesis.

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“…In clinical studies, expression of TSHR has been shown to correlate with the degree of iodine trapping (Edmonds et al 1977), and with efficacy of ablation (Fallahi et al et al 2012). Further, both positive and negative regulation of NIS mRNA in response to TSHR stimulation has been demonstrated in human thyroid cells (Saito et al 1997, Bruno et al 2005. Interestingly, TSHR stimulation also increases the sensitivity of 18 F-FDG-PET imaging in the detection of residual metastatic disease, again suggesting that TSHR stimulation increases mitotic activity and glucose utilization within malignant thyrocytes (Leboulleux et al 2009).…”

Section: Current Therapeutic Targeting Of Tshr In Dtcmentioning

confidence: 99%

“…Activation of Gα s stimulates adenylate cyclase and activates the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway with wellestablished mitogenic effects, whereas Gα q stimulation results in the activation of protein kinase B and mitogenactivated protein kinase (MAPK) pathways (Morshed et al 2009). The downstream effects are to increase the transcription of thyroid-specific genes, particularly controlling iodine uptake, synthesis of thyroglobulin and thyroperoxidase, with the end result of thyroid hormone production (Roger et al 1988, Bruno et al 2005. The regulation of thyrocyte growth has been extensively studied using in vitro models; however, it is well recognized that human in vivo confirmation of any such model is paramount (Kimura et al 2001).…”

Section: Tsh and Intracellular Growth Signalingmentioning

confidence: 99%

“…Bruno and coworkers (Bruno et al 2005) demonstrated in vivo in humans that TSH regulates the transcription of NIS (SLC5A5), thyroglobulin (TG), thyroperoxidase (TPO) and paired box 8 (PAX8) mRNA, but not TSHR, pendrin (SLC26A4) or thyroid transcription factor 1 (NKX2-1). Importantly, they showed that absence of TSH due to suppression from exogenous hyperthyroidism does not reduce TSHR mRNA.…”

Section: Tsh and Intracellular Growth Signalingmentioning

confidence: 99%

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Targeting the TSH receptor in thyroid cancer

Rowe¹,

Paul²,

Gedye³

et al. 2017

Endocrine-Related Cancer

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Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid-stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid-stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for individual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted.

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Modulation of Thyroid-Specific Gene Expression in Normal and Nodular Human Thyroid Tissues from Adults: An in Vivo Effect of Thyrotropin

Cited by 45 publications

References 24 publications

A molecular analysis and long-term follow-up of two siblings with severe congenital hypothyroidism carrying the IVS30+1G>T intronic thyroglobulin mutation

A molecular analysis and long-term follow-up of two siblings with severe congenital hypothyroidism carrying the IVS30+1G>T intronic thyroglobulin mutation

Different expression of TSH receptor and NIS genes in thyroid cancer: role of epigenetics

Targeting the TSH receptor in thyroid cancer

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