Dataset Information

Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer.

ABSTRACT: Background: Protective effects of vitamin D have been reported in autoimmune and malignant thyroid diseases, though little is known about the underlying mechanism. Sirtuin 1 histon deacethylase (SIRT1) links the vitamin D pathway with regulation of transcription factor FOXO3a, a key player in cell cycle regulation and apoptosis. Aim of the present study was to investigate common single nucleotide polymorphisms (SNP's) in FOXO3a gene in respect to thyroid diseases, as well as to evaluate the hypothesis of Sirtuin1-FOXO3a interaction being a mediator of anti-proliferative vitamin D effects. Methods: The SNP's FOXO3a rs4946936/rs4945816/rs9400239 were genotyped in 257 patients with differentiated thyroid carcinoma (DTC), 139 patients with Hashimoto thyroiditis (HT) and 463 healthy controls (HC). Moreover, T-helper cells of HC and papillary thyroid cancer cell line BCPAP were incubated with 1,25(OH)2D3 and/or SIRT1 inhibitor Ex-527 in order to elucidate SIRT1- dependent vitamin D effects on cell proliferation and FOXO3a gene expression in vitro. Results: Patients with DTC tended to carry more often allele C in FOXO3a rs4946936 in comparison to HC (pcorrected = pc = 0.08). FOXO3a rs9400239T and rs4945816C was more frequent in HT in comparison to HC (pc = 0.02 and pc = 0.01, respectively). In both DTC and HT, we could not find a correlation of FOXO3a SNP's with vitamin D status. However, on in vitro level, 1,25(OH)2D3 showed an anti-proliferative effect in both T-helper cells and BCPAP, that was blocked by SIRT1 inhibition (T-helper cells: p = 0.0059, BCPAP: p = 0.04) and accompanied by elevated FOXO3a gene expression in T-helper cells (p = 0.05). Conclusions: FOXO3a rs9400239T and rs4945816C may constitute risk factors for HT, independent of the vitamin D status.This indicates the implication of FOXO3a in pathogenesis of autoimmune thyroid diseases. The dependency of anti-proliferative vitamin D effects on SIRT1 activity further suggests a key role of vitamin D-SIRT1-FOXO3a axis for protective vitamin D effects.

SUBMITTER: Roehlen N

PROVIDER: S-EPMC6142903 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer.

Roehlen Natascha N Doering Claudia C Hansmann Martin-Leo ML Gruenwald Frank F Vorlaender Christian C Bechstein Wolf Otto WO Holzer Katharina K Badenhoop Klaus K Penna-Martinez Marissa M

Frontiers in endocrinology 20180911

<b>Background:</b> Protective effects of vitamin D have been reported in autoimmune and malignant thyroid diseases, though little is known about the underlying mechanism. Sirtuin 1 histon deacethylase (SIRT1) links the vitamin D pathway with regulation of transcription factor FOXO3a, a key player in cell cycle regulation and apoptosis. Aim of the present study was to investigate common single nucleotide polymorphisms (SNP's) in <i>FOXO3a</i> gene in respect to thyroid diseases, as well as to eva ...[more]

PMID: 30271381

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Project description:BACKGROUND: Hashimoto's thyroiditis (HT) has been found to coexist with differentiated thyroid cancer (DTC) in surgical specimens, but an association between the two conditions has been discounted by the medical literature. Therefore, we performed this study to determine any potential relationship between HT and the risk of developing DTC. METHODS: We collected data for thyrotropin (TSH), thyroxine (T4), thyroid peroxidase antibody (TPO-Ab) titers, surgical pathology, and weight-based levothyroxine (LT4) replacement dose for patients who were referred for thyroid surgery. Patients with HT at final pathology were studied further. To estimate thyroid function, patients with preoperative hypothyroid HT (Hypo-HT) were divided into three equal groups based on their LT4 replacement: LT4-Low (<0.90 ?g/kg), LT4-Mid (0.90-1.43 ?g/kg), and LT4-High (>1.43 ?g/kg). A group of preoperatively euthyroid (Euth-HT) patients but with HT by pathology was also studied. All subjects were also grouped based on their TPO-Ab titer in TPO-high (titer >1:1000) or TPO-low/negative (titer <1:1000 or undetectable) groups. The relationship of HT and DTC was studied extensively. RESULTS: Of 2811 subjects, 582 had HT on surgical pathology, 365 of whom were Euth-HT preoperatively. DTC was present in 47.9% of the Euth-HT, in 59.7% of LT4-Low, 29.8% of LT4-Mid, and 27.9% of LT4-High groups. The relative risk (RR) for DTC was significantly elevated for the Euth-HT and LT4-Low groups (p<0.001), but not for the LT4-Mid or LT4-High replacement dose groups. TPO-low/negative status conferred an increased RR in the Euth-HT and LT4-Low replacement dose groups (p<0.001 both), while TPO-high status decreased it in Euth-HT group (p<0.05) and made it nonsignificant in the LT4-Low group. CONCLUSIONS: HT pathology increases the risk for DTC only in euthyroid subjects and those with partially functional thyroid glands (LT4-Low) but not in fully hypothyroid HT (LT4-Mid and LT4-High). High TPO-Ab titers appear to protect against DTC in patients with HT.

Project description:BackgroundPrevious models for differentiating benign and malignant thyroid nodules(TN) have predominantly focused on the characteristics of the nodules themselves, without considering the specific features of the thyroid gland(TG) in patients with Hashimoto's thyroiditis(HT). In this study, we analyzed the clinical and ultrasound radiomics(USR) features of TN in patients with HT and constructed a model for differentiating benign and malignant nodules specifically in this population.MethodsWe retrospectively collected clinical and ultrasound data from 227 patients with TN and concomitant HT(161 for training, 66 for testing). Two experienced sonographers delineated the TG and TN regions, and USR features were extracted using Python. Lasso regression and logistic analysis were employed to select relevant USR features and clinical data to construct the model for differentiating benign and malignant TN. The performance of the model was evaluated using area under the curve(AUC), calibration curves, and decision curve analysis(DCA).ResultsA total of 1,162 USR features were extracted from TN and the TG in the 227 patients with HT. Lasso regression identified 14 features, which were used to construct the TN score, TG score, and TN+TG score. Univariate analysis identified six clinical predictors: TI-RADS, echoic type, aspect ratio, boundary, calcification, and thyroid function. Multivariable analysis revealed that incorporating USR scores improved the performance of the model for differentiating benign and malignant TN in patients with HT. Specifically, the TN+TG score resulted in the highest increase in AUC(from 0.83 to 0.94) in the clinical prediction model. Calibration curves and DCA demonstrated higher accuracy and net benefit for the TN+TG+clinical model.ConclusionUSR features of both the TG and TN can be utilized for differentiating benign and malignant TN in patients with HT. These findings highlight the importance of considering the entire TG in the evaluation of TN in HT patients, providing valuable insights for clinical decision-making in this population.

Dataset Information

Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer.

Publications

Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer.

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