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The targeted inactivation of Men1 gene exacerbates Ret/PTC3-induced thyroid neoplastic transformation

AutorSelmi-Ruby, Samia; Obregón, María Jesús; Borson-Chazot, Françoise
Fecha de publicación2014
CitaciónETA 2014
ResumenMultiple Endocrine Neoplasia type1 is an inherited predisposition syndrome characterized by an increased risk of endocrine tumors. In a previous study, we found that menin acts as a negative regulator controlling the thyroid growth. To explore the tumor suppressor function of menin, we analyzed whether thyroid-selective inactivation of Men1 gene affects Ret/PTC3-driven neoplastic transformation. Mice with Men1-disruption selectively in thyrocytes (Men1flox/floxThyrCre) were generated by crossing transgenic ThyrCre mice (expressing the Cre selectively in thyrocytes) with mice carrying Men1floxalleles. Men1flox/floxThyrCre mice were then crossed with mice expressing the Ret-PTC3 oncogene selectively in the thyroid (RP3mice). Thyroid phenotype of mice was analyzed at 4, 8 and 12 months of age. RP3-induced thyroid hypertrophy was transiently reduced and followed by a significant increase in aging Men1flox/floxThyrCre/RP3 mice in comparison with aged-matched RP3 littermates. At 4, 8 and12 months of age, hormonal status analyses disclosed a decrease of serum T4 and T3 associated with a marked increase in serum TSH concentrations. The functional activity of the thyroid assessed by measurements of the expression level of thyroid-specific genes appeared reduced in Men1flox/floxThyrCre/RP3 mice compared to that of age-matched RP3 littermates. In aging Men1flox/floxThyrCre/RP3 mice, morphological examinations of the thyroid showed a profound tissue remodeling associated with the occurrence of mesenchymal structures. This observation was evidenced by a 2-fold-increase in vimentin and fibronectin1 without significant decrease in E-cadherin mRNA levels. However, a 3-fold-increase in Sip1 and Snail mRNA levels known to be E-cadherin repressors involved in the epithelial-to-mesenchymal transition (EMT) was observed in Men1flox/ floxThyrCre/RP3 mice compared to that of RP3 littermates. Our data indicate that tumors developped following Ret/PTC3 expression are susceptible to undergo EMT in response to the targeted-inactivation of the Men1 gene. In conclusion, we show for the first time that Men1 gene acts as a tumor suppressor in Ret/PTC3-driven thyroid neoplastic transformation.
DescripciónResumen del trabajo presentado al 38th Annual Meeting of the European Thyroid Association celebrado en Santiago de Compostela (España) del 6 al 10 de septiembre de 2014.-- et al.
Aparece en las colecciones: (IIBM) Comunicaciones congresos
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