Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer
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 c...
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Frontiers Media S.A.
2018-09-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fendo.2018.00527/full |
| _version_ | 1819319608789696512 |
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| author | Natascha Roehlen Claudia Doering Martin-Leo Hansmann Frank Gruenwald Christian Vorlaender Wolf Otto Bechstein Katharina Holzer Klaus Badenhoop Marissa Penna-Martinez |
| author_facet | Natascha Roehlen Claudia Doering Martin-Leo Hansmann Frank Gruenwald Christian Vorlaender Wolf Otto Bechstein Katharina Holzer Klaus Badenhoop Marissa Penna-Martinez |
| author_sort | Natascha Roehlen |
| collection | DOAJ |
| description | 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. |
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| language | English |
| last_indexed | 2024-12-24T11:06:24Z |
| publishDate | 2018-09-01 |
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| spelling | doaj.art-e3870b8a0a2e45b2a1748876ee375d332022-12-21T16:58:38ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922018-09-01910.3389/fendo.2018.00527398690Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid CancerNatascha Roehlen0Claudia Doering1Martin-Leo Hansmann2Frank Gruenwald3Christian Vorlaender4Wolf Otto Bechstein5Katharina Holzer6Klaus Badenhoop7Marissa Penna-Martinez8Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Frankfurt, Frankfurt, GermanySenckenberg Institute for Pathology, University Frankfurt, Frankfurt, GermanySenckenberg Institute for Pathology, University Frankfurt, Frankfurt, GermanyDepartment of Nuclear Medicine, University Frankfurt, Frankfurt, GermanyDepartment of General Surgery, Buergerhospital Frankfurt, Frankfurt, GermanyDepartment of General Surgery, University Frankfurt, Frankfurt, GermanySection of Endocrine Surgery, Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, GermanyDivision of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Frankfurt, Frankfurt, GermanyDivision of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Frankfurt, Frankfurt, GermanyBackground: 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.https://www.frontiersin.org/article/10.3389/fendo.2018.00527/fullsirtuin1FOXO3avitamin Dvitamin D receptordifferentiated thyroid carcinomaHashimoto's thyroiditis |
| spellingShingle | Natascha Roehlen Claudia Doering Martin-Leo Hansmann Frank Gruenwald Christian Vorlaender Wolf Otto Bechstein Katharina Holzer Klaus Badenhoop Marissa Penna-Martinez Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer Frontiers in Endocrinology sirtuin1 FOXO3a vitamin D vitamin D receptor differentiated thyroid carcinoma Hashimoto's thyroiditis |
| title | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
| title_full | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
| title_fullStr | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
| title_full_unstemmed | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
| title_short | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
| title_sort | vitamin d foxo3a and sirtuin1 in hashimoto s thyroiditis and differentiated thyroid cancer |
| topic | sirtuin1 FOXO3a vitamin D vitamin D receptor differentiated thyroid carcinoma Hashimoto's thyroiditis |
| url | https://www.frontiersin.org/article/10.3389/fendo.2018.00527/full |
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