TY  - JOUR
A1  - Röhlen, Natascha
A1  - Döring, Claudia
A1  - Hansmann, Martin-Leo
A1  - Grünwald, Frank
A1  - Vorländer, Christian
A1  - Bechstein, Wolf Otto
A1  - Holzer, Katharina
A1  - Badenhoop, Klaus
A1  - Penna Martinez, Marissa
T1  - Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and differentiated Thyroid cancer
T2  - Frontiers in endocrinology
N2  - 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.
KW  - sirtuin1
KW  - FOXO3a
KW  - vitamin D
KW  - vitamin D receptor
KW  - differentiated thyroid carcinoma
KW  - Hashimoto’s thyroiditis
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47453
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-474539
SN  - 1664-2392
N1  - Copyright © 2018 Roehlen, Doering, Hansmann, Gruenwald, Vorlaender, Bechstein, Holzer, Badenhoop and Penna-Martinez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
VL  - 9
IS  - Art. 527
SP  - 1
EP  - 9
PB  - Frontiers Research Foundation
CY  - Lausanne
ER  -