Down‐regulation of NR4A1 in follicular thyroid carcinomas is restored following lithium treatment

Abstract

Summary Introduction The identification of follicular thyroid adenoma‐associated transcripts will lead to a better understanding of the events involved in pathogenesis and progression of follicular tumours. Using Serial Analysis of Gene Expression, we identified five genes that are absent in a malignant follicular thyroid carcinoma (FTC) library, but expressed in follicular adenoma (FTA) and normal thyroid libraries. Methods NR4A1, one of the five genes, was validated in a set of 27 normal thyroid tissues, 10 FTAs and 14 FTCs and three thyroid carcinoma cell lines by real time PCR. NR4A1 can be transiently increased by a variety of stimuli, including lithium, which is used as adjuvant therapy of thyroid carcinoma with 131I. We tested if lithium could restore NR4A1 expression. The expression of other genes potentially involved in the same signalling pathway was tested. To this end, lithium was used at different concentration (10 mm or 20 mm) and time (2 h and 24 h) and the level of expression was tested by quantitative PCR. We next tested if Lithium could affect cell growth and apoptosis. Results We observed that NR4A1 expression was under‐expressed in most of the FTCs investigated, compared with expression in normal thyroid tissues and FTAs. We also found a positive correlation between NR4A1 and FOSB gene expression. Lithium induced NR4A1 and FOSB expression, reduced CCDN1 expression, inhibited cell growth and triggered apoptosis in a FTC cell line. Conclusions NR4A1 is under‐expressed in most of FTCs. The loss of expression of both NR4A1 and the Wnt pathway gene FOSB was correlated with malignancy. This is consistent with the hypothesis that its loss of expression is part of the transformation process of FTCs, either as a direct or indirect consequence of Wnt pathway alterations. Lithium restores NR4A1 expression, induces apoptosis and reduces cell growth. These findings may explain a possible molecular mechanism of lithium's therapeutic action.

Molecular signatures of thyroid follicular neoplasia

“…The coordinated down-regulation of NR4A1 and NR4A3 and JUN, FOSB, and CITED2 is striking, since these factors have previously been shown to be part of a common proapoptotic and cancer-predisposing pathways (Mullican et al 2007). Moreover, this finding is supported by two recent studies where NR4A1 was found to be down-regulated in FC (Fryknas et al 2006, Camacho et al 2009). NR4A1 and NR4A3 also known as Nur77 and Nor-1 respectively are homologous orphan nuclear receptors that regulate the transcription of a common set of target genes (Li et al 2006), and both have been described as homeostatic regulators of proliferation and apoptosis (Moll et al 2006, Zhan et al 2008.…”

The RET p.G533C Mutation Confers Predisposition to Multiple Endocrine Neoplasia Type 2A in a Brazilian Kindred and Is Able to Induce a Malignant Phenotype In Vitro and In Vivo

“…Cell proliferation rate was measured with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay as described (16). In brief, PCCL3 cells (10 4 ) expressing RET mutants or Wt were seeded in quintuplicate.…”

Inhibitions of thyroidal and extra-thyroidal T3, T4 and thyroperoxidase profiles with elevations of TSH following lithium treatment in adult and aged rats

“…It is also known that target of lithium blocks the c-Jun apoptotic stress by inhibiting glycogen-synthase kinase-3 (GSK-3) and thereby protects neurons (9). In case of follicular thyroid carcinoma, down regulation of NR4A1 is restored following lithium treatment (41). Thus, apart from the above-cited therapeutic and beneficial effects, lithium has also untoward effects on thyroid function in rats.…”