Classification moléculaire des tumeurs thyroïdiennes: intérêts et limites de l'approche transcriptormique

Le transcriptome permet d\u27avoir une vision globale des fonctions dérégulées dans une classe tumorale. » L\u27analyse du transcriptome permet d\u27identifier les processus tumoraux initiaux, mais aussi les réactions du tissu environnant (infiltrats lymphocytaires). » Il existe une meilleure corrélation entre le statut mutationnel et le transcriptome d\u27une tumeur qu\u27entre le statut mutationnel et l\u27histologie de cette tumeur. » L\u27identification de biomarqueurs spécifiques de classe n\u27est pertinente que si le transcriptome de l\u27ensemble des classes pathologiques de l\u27organe est exploré. » Le profil d\u27expression de biomarqueurs ciblés présente un réel potentiel diagnostique pour les classes intermédiaires de pathologies

Marked Hyperthyroxinemia During Amiodarone Treatment Revealing Thyroid Hormone Resistance Syndrome

International audienc

Les microARNs

MiRNAs are small non-coding RNAs ensuring the post-transcriptional regulation of gene expression. Their expression is tissue-specific and some miRNAs have diagnostic and / or prognostic value for tumor classes. MiRNAs are involved in tumorigenesis by two mechanisms: amplification or deletion of chromosomal regions containing clusters of genes encoding miRNAs (quantitative effect) or modification of the effects of miRNAs on their target genes by mutation in the region of interaction with the mRNA (qualitative effect). Their specificity, the possibility for miRNA measurement in blood, must now lead to consider miRNAs as markers for therapeutic management. A better understanding of the different regulatory mechanisms involving miRNAs will also consider new therapeutic approaches

Micro-ARNs dans les tumeurs folliculaires de la thyroïde

Key pointsMiRNAs are small noncoding RNA ensuring post-transcriptional regulation of gene expression. Their expression is tissue-specific and some miRNAs have diagnostic and/or prognostic interest for tumor classes. MiRNAs are involved in tumoral process in quantitative (amplification, deletion of chromosomal regions) or qualitative terms (mutation in the miRNA or in the corresponding site of interaction in the mRNA). Overexpression of three miRNAs (miR-146b, miR-221 and miR-222) correlates with the development of papillary thyroid tumors. Polymorphisms in the c-kit gene or in that encoding miR-146a are susceptibility factors for the development of papillary thyroid tumors. Points essentiels Les micro-ARNs (miRNAs) sont des petits ARN non codant assurant la régulation post-transcriptionnelle de l’expression génique. Leur expression est tissu-spécifique et certains miRNAs ont une valeur diagnostique et/ou pronostique de classes tumorales. Les miRNAs sont impliqués dans les processus tumoraux par deux mécanismes : amplification ou délétion de régions chromosomiques renfermant des clusters de gènes codant des miRNAs (effet quantitatif) ou modification des effets des miRNAs sur leur gènes cibles par mutation dans le site d’interaction avec les ARNm (effet qualitatif). La surexpression de trois miRNAs (miR-146b, miR-221 et miR-222) est corrélée au développement des tumeurs papillaires de la thyroïde. Des polymorphismes dans le gène c-Kit ou dans celui codant pour miR-146a sont des facteurs de susceptibilité au développement des tumeurs papillaires de la thyroïde

A Child with Resistance to Thyroid Hormone without Thyroid Hormone Receptor Gene Mutation: A 20-Year Follow-Up

We report here the 20-year follow-up study of a male subject diagnosed at 15 months of age as a sporadic case of pituitary resistance to thyroid hormone on the combination of clinical hyperthyroidism, elevated serum thyroid hormone (TH) levels and inappropriate thyrotropin (TSH). On d-thyroxine (D-T4) therapy from 30 months of age to 12.5 years, hyperactivity and hyperthyroid signs and symptoms as well as growth abnormalities improved, serum l-thyroxine (L-T4) enantiomer normalized, and basal and stimulated TSH decreased significantly without complete suppression. After 8 years off D-T4, at 20 years of age, clinical status was normal despite persisting high TH levels and inappropriate TSH. Evolution of serum markers of TH action and echocardiography measurements followed up from 15 months to 20 years of age either in basal condition or on triiodothyronine (T3), as well as the sequential determination of bone mineral density suggest differences in the tissue responses to T3: normal in bone with a high remodelling rate, heterogeneity for various hepatic markers, and decreased at heart level. No mutations were found in the coding sequence of TRβ1, TRβ2, TRα1, RXRγ, SMRT, NCoR1, and NCoA1. In this patient the putative long-term effects of the persisting high bone resorption are unknown

Estrogen-related receptor α and PGC-1-related coactivator constitute a novel complex mediating the biogenesis of functional mitochondria

Mitochondrial biogenesis, which depends on nuclear as well as mitochondrial genes, occurs in response to increased cellular ATP demand. The nuclear transcriptional factors, estrogen-related receptor α (ERRα) and nuclear respiratory factors 1 and 2, are associated with the coordination of the transcriptional machinery governing mitochondrial biogenesis, whereas coactivators of the peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) family serve as mediators between the environment and this machinery. In the context of proliferating cells, PGC-1-related coactivator (PRC) is a member of the PGC-1 family, which is known to act in partnership with nuclear respiratory factors, but no functional interference between PRC and ERRα has been described so far. We explored three thyroid cell lines, FTC-133, XTC.UC1 and RO 82 W-1, each characterized by a different mitochondrial content, and studied their behavior towards PRC and ERRα in terms of respiratory efficiency. Overexpression of PRC and ERRα led to increased respiratory chain capacity and mitochondrial mass. The inhibition of ERRα decreased cell growth and respiratory chain capacity in all three cell lines. However, the inhibition of PRC and ERRα produced a greater effect in the oxidative cell model, decreasing the mitochondrial mass and the phosphorylating respiration, whereas the nonphosphorylating respiration remained unchanged. We therefore hypothesize that the ERRα–PRC complex plays a role in arresting the cell cycle through the regulation of oxidative phosphorylation in oxidative cells, and through some other pathway in glycolytic cells

Death-associated protein 3 is overexpressed in human thyroid oncocytic tumours

Background: The human death-associated protein 3 (hDAP3) is a GTP-binding constituent of the small subunit of the mitochondrial ribosome with a pro-apoptotic function.Methods: A search through publicly available microarray data sets showed 337 genes potentially coregulated with the DAP3 gene. The promoter sequences of these 337 genes and 70 out of 85 mitochondrial ribosome genes were analysed in silico with the DAP3 gene promoter sequence. The mitochondrial role of DAP3 was also investigated in the thyroid tumours presenting various mitochondrial contents. Results: The study revealed nine transcription factors presenting enriched motifs for these gene promoters, five of which are implicated in cellular growth (ELK1, ELK4, RUNX1, HOX11-CTF1, TAL1-ternary complex factor 3) and four in mitochondrial biogenesis (nuclear respiratory factor-1 (NRF-1), GABPA, PPARG-RXRA and estrogen-related receptor alpha (ESRRA)). An independent microarray data set showed the overexpression of ELK1, RUNX1 and ESRRA in the thyroid oncocytic tumours. Exploring the thyroid tumours, we found that DAP3 mRNA and protein expression is upregulated in tumours presenting a mitochondrial biogenesis compared with the normal tissue. ELK1 and ESRRA were also showed upregulated with DAP3. Conclusion: ELK1 and ESRRA may be considered as potential regulators of the DAP3 gene expression. DAP3 may participate in mitochondrial maintenance and play a role in the balance between mitochondrial homoeostasis and tumourigenesis