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Cell and Molecular Biology of Thyroid Disorders
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Cell and Molecular Biology of Thyroid Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (25 February 2019) | Viewed by 93495

Special Issue Editor

Dr. Daniela Grimm

E-Mail Website
Guest Editor
1. Institute of Biomedicine, Aarhus University, Ole Worms Allé 4, 8000 Aarhus, Denmark
2. Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University Magdeburg, Pfälzerplatz 2, 39106 Magdeburg, Germany
Interests: breast cancer; thyroid cancer; prostate cancer; cell biology; gravitational biology; space medicine; tissue engineering; pharmacology; apoptosis; SOX transcription factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous special issue "Current Knowledge in Thyroid Cancer—From Bench to Bedside".

A great majority of cells of the human organism stay under the influence of thyroid hormones. They control cellular metabolism and protein synthesis. Therefore, a proper performance of the thyroid gland and its cells is of highest importance for the health of a human being. Very often, iodine deficiency causes malfunction of the thyroid and plays a role in thyroid cancer carcinogenesis. Both, hyperthyroidism and hypothyroidism have detrimental effects on our health.

The topic of this Special Issue is cell and molecular biology of thyroid disorders. There has been exciting progress in understanding the molecular mechanisms of thyroid diseases in recent years. Molecular alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for thyroid cancer. Specific biomarkers, as well as cancer-specific changes in gene expression patterns and alterations of the protein content had been identified.

Studies using animal or cell culture models to investigate molecular mechanisms or thyroid diseases will be published. This Special Issue will also cover reports on patients, providing novel mechanistic insights into the underlying pathogenesis or new aspects that may impact clinical therapy.

Dr. Daniela Grimm
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Thyroid diseases
  • Thyroid Cancer
  • Cell Biology
  • Cell Signaling
  • Iodine deficiency
  • Apoptosis
  • Biomarker

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Published Papers (19 papers)

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Editorial

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8 pages, 226 KiB  
Editorial
Cell and Molecular Biology of Thyroid Disorders
by Daniela Grimm
Int. J. Mol. Sci. 2019, 20(12), 2895; https://doi.org/10.3390/ijms20122895 - 13 Jun 2019
Cited by 11 | Viewed by 3606
Abstract
The thyroid is a hormone gland involved in metabolism, regulatory functions, growth, and development of the human organism [...] Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)

Research

Jump to: Editorial, Review

14 pages, 3035 KiB  
Article
Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells
by Dmytro Starenki, Nadiya Sosonkina, Seung-Keun Hong, Ricardo V. Lloyd and Jong-In Park
Int. J. Mol. Sci. 2019, 20(9), 2069; https://doi.org/10.3390/ijms20092069 - 26 Apr 2019
Cited by 38 | Viewed by 3921
Abstract
We previously reported that upregulation of mortalin (HSPA9/GRP75), the mitochondrial HSP70 chaperone, facilitates tumor cell proliferation and survival in human medullary thyroid carcinoma (MTC), proposing mortalin as a novel therapeutic target for MTC. In this report, we show that mortalin is also upregulated [...] Read more.
We previously reported that upregulation of mortalin (HSPA9/GRP75), the mitochondrial HSP70 chaperone, facilitates tumor cell proliferation and survival in human medullary thyroid carcinoma (MTC), proposing mortalin as a novel therapeutic target for MTC. In this report, we show that mortalin is also upregulated in other thyroid tumor types, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and anaplastic thyroid carcinoma (ATC), and that mortalin depletion can effectively induce growth arrest and cell death in human PTC (TPC-1), FTC (FTC133), and ATC (8505C and C643) cells in culture. Intriguingly, mortalin depletion induced varied effects on cell cycle arrest (G0/G1 phase arrest in TPC-1 and C643, G2/M phase arrest in 8505C, and mild G2/M phase arrest with increased sub-G0/G1 population in FTC133) and on the levels of TP53, E2F-1, p21CIP1, p27KIP1, and poly (ADP-ribose) polymerase cleavage in these cells, suggesting that thyroid tumor cells respond to mortalin depletion in a cell type-specific manner. In these cells, we also determined the efficacy of triphenyl-phosphonium-carboxy-proxyl (Mito-CP) because this mitochondria-targeted metabolism interfering agent exhibited similar tumor suppressive effects as mortalin depletion in MTC cells. Indeed, Mito-CP also induced robust caspase-dependent apoptosis in PTC and ATC cell lines in vitro, exhibiting IC50 lower than PLX4032 in 8505C cells and IC50 lower than vandetanib and cabozantinib in TPC-1 cells. Intriguingly, Mito-CP-induced cell death was partially rescued by mortalin overexpression, suggesting that Mito-CP may inactivate a mechanism that requires mortalin function. These findings support the significance of mortalin and mitochondrial activity in a broad spectrum of thyroid cancer. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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13 pages, 1498 KiB  
Article
PFKFB2 Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas
by Mateus Camargo Barros-Filho, Larissa Barreto Menezes de Lima, Mariana Bisarro dos Reis, Julia Bette Homem de Mello, Caroline Moraes Beltrami, Clóvis Antonio Lopes Pinto, Luiz Paulo Kowalski and Silvia Regina Rogatto
Int. J. Mol. Sci. 2019, 20(6), 1334; https://doi.org/10.3390/ijms20061334 - 16 Mar 2019
Cited by 10 | Viewed by 3755
Abstract
Despite the low mortality rates, well-differentiated thyroid carcinomas (WDTC) frequently relapse. BRAF and TERT mutations have been extensively related to prognosis in thyroid cancer. In this study, the methylation levels of selected CpGs (5-cytosine-phosphate-guanine-3) comprising a classifier, previously reported by our group, were [...] Read more.
Despite the low mortality rates, well-differentiated thyroid carcinomas (WDTC) frequently relapse. BRAF and TERT mutations have been extensively related to prognosis in thyroid cancer. In this study, the methylation levels of selected CpGs (5-cytosine-phosphate-guanine-3) comprising a classifier, previously reported by our group, were assessed in combination with BRAF and TERT mutations. We evaluated 121 WDTC, three poorly-differentiated/anaplastic thyroid carcinomas (PDTC/ATC), 22 benign thyroid lesions (BTL), and 13 non-neoplastic thyroid (NT) tissues. BRAF (V600E) and TERT promoter (C228T and C250T) mutations were tested by pyrosequencing and Sanger sequencing, respectively. Three CpGs mapped in PFKFB2, ATP6V0C, and CXXC5 were evaluated by bisulfite pyrosequencing. ATP6V0C hypermethylation and PFKFB2 hypomethylation were detected in poor-prognosis (PDTC/ATC and relapsed WDTC) compared with good-prognosis (no relapsed WDTC) and non-malignant cases (NT/BTL). CXXC5 was hypomethylated in both poor and good-prognosis cases. Shorter disease-free survival was observed in WDTC patients presenting lower PFKFB2 methylation levels (p = 0.004). No association was observed on comparing BRAF (60.7%) and TERT (3.4%) mutations and prognosis. Lower PFKFB2 methylation levels was an independent factor of high relapse risk (Hazard Ratio = 3.2; CI95% = 1.1–9.5). PFKFB2 promoter methylation analysis has potential applicability to better stratify WDTC patients according to the recurrence risk, independently of BRAF and TERT mutations. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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14 pages, 1459 KiB  
Article
MiR-19a Overexpression in FTC-133 Cell Line Induces a More De-Differentiated and Aggressive Phenotype
by Giovanna Calabrese, Anna Dolcimascolo, Filippo Torrisi, Agata Zappalà, Rosario Gulino and Rosalba Parenti
Int. J. Mol. Sci. 2018, 19(12), 3944; https://doi.org/10.3390/ijms19123944 - 07 Dec 2018
Cited by 14 | Viewed by 3212
Abstract
In recent years, microRNAs (miRNAs) have received increasing attention for their important role in tumor initiation and progression. MiRNAs are a class of endogenous small non-coding RNAs that negatively regulate the expression of several oncogenes or tumor suppressor genes. MiR-19a, a component of [...] Read more.
In recent years, microRNAs (miRNAs) have received increasing attention for their important role in tumor initiation and progression. MiRNAs are a class of endogenous small non-coding RNAs that negatively regulate the expression of several oncogenes or tumor suppressor genes. MiR-19a, a component of the oncogenic miR-17-92 cluster, has been reported to be highly expressed only in anaplastic thyroid cancer, the most undifferentiated, aggressive and lethal form of thyroid neoplasia. In this work, we evaluated the putative contribution of miR-19a in de-differentiation and aggressiveness of thyroid tumors. To this aim, we induced miR-19a expression in the well-differentiated follicular thyroid cancer cell line and evaluated proliferation, apoptosis and gene expression profile of cancer cells. Our results showed that miR-19a overexpression stimulates cell proliferation and alters the expression profile of genes related to thyroid cell differentiation and aggressiveness. These findings not only suggest that miR-19a has a possible involvement in de-differentiation and malignancy, but also that it could represent an important prognostic indicator and a good therapeutic target for the most aggressive thyroid cancer. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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16 pages, 2861 KiB  
Article
OPNa Overexpression Is Associated with Matrix Calcification in Thyroid Cancer Cell Lines
by Luciana B. Ferreira, Raquel T. Lima, Ana Clara Santos da Fonseca Bastos, Andreia M. Silva, Catarina Tavares, Ana Pestana, Elisabete Rios, Catarina Eloy, Manuel Sobrinho-Simões, Etel R. P. Gimba and Paula Soares
Int. J. Mol. Sci. 2018, 19(10), 2990; https://doi.org/10.3390/ijms19102990 - 30 Sep 2018
Cited by 16 | Viewed by 3816
Abstract
Osteopontin (OPN) spliced variants (OPN-SV: OPNa, OPNb, and OPNc) are aberrantly expressed in tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common type of thyroid cancer (TC). PTC often presents with desmoplasia [...] Read more.
Osteopontin (OPN) spliced variants (OPN-SV: OPNa, OPNb, and OPNc) are aberrantly expressed in tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common type of thyroid cancer (TC). PTC often presents with desmoplasia and dystrophic calcification, including psammoma bodies (PB). This work aimed to investigate total OPN (tOPN) and OPN-SV expression and their association with the presence of PB in the PTC classical variants (cPTC), as well as the involvement of OPN-SV in matrix calcification of TC cell lines. We found that cPTC samples presenting PB showed higher OPN expression levels. In TC cell lines, OPNa overexpression promotes higher matrix calcification and collagen synthesis when compared to that of clones overexpressing OPNb or OPNc. In response to OPN knockdown, calcification was inhibited, paralleled with the downregulation of calcification markers. In conclusion, our data evidenced that OPN expression is associated with the presence of PB in cPTC samples. Among the OPN-SV, OPNa is the main contributor to matrix calcification in tested TC cells, providing clues to a better understanding on the biology and ethiopathogenesis of the calcification process in TC cells. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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15 pages, 2463 KiB  
Article
Metabolomic Alterations in Thyrospheres and Adherent Parental Cells in Papillary Thyroid Carcinoma Cell Lines: A Pilot Study
by Paola Caria, Laura Tronci, Tinuccia Dettori, Federica Murgia, Maria Laura Santoru, Julian L. Griffin, Roberta Vanni and Luigi Atzori
Int. J. Mol. Sci. 2018, 19(10), 2948; https://doi.org/10.3390/ijms19102948 - 27 Sep 2018
Cited by 15 | Viewed by 3082
Abstract
Papillary thyroid carcinoma (PTC), is characterized by a heterogeneous group of cells, including cancer stem cells (CSCs), crucially involved in tumor initiation, progression and recurrence. CSCs appear to have a distinct metabolic phenotype, compared to non-stem cancer cells. How they adapt their metabolism [...] Read more.
Papillary thyroid carcinoma (PTC), is characterized by a heterogeneous group of cells, including cancer stem cells (CSCs), crucially involved in tumor initiation, progression and recurrence. CSCs appear to have a distinct metabolic phenotype, compared to non-stem cancer cells. How they adapt their metabolism to the cancer process is still unclear, and no data are yet available for PTC. We recently isolated thyrospheres, containing cancer stem-like cells, from B-CPAP and TPC-1 cell lines derived from PTC of the BRAF-like expression profile class, and stem-like cells from Nthy-ori3-1 normal thyreocyte-derived cell line. In the present study, gas chromatography/mass spectrometry metabolomic profiles of cancer thyrospheres were compared to cancer parental adherent cells and to non cancer thyrospheres profiles. A statistically significant decrease of glycolytic pathway metabolites and variations in Krebs cycle metabolites was found in thyrospheres versus parental cells. Moreover, cancer stem-like cells showed statistically significant differences in Krebs cycle intermediates, amino acids, cholesterol, and fatty acids content, compared to non-cancer stem-like cells. For the first time, data are reported on the metabolic profile of PTC cancer stem-like cells and confirm that changes in metabolic pathways can be explored as new biomarkers and targets for therapy in this tumor. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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11 pages, 2123 KiB  
Article
Whole Exome Sequencing Identifies a Novel Hedgehog-Interacting Protein G516R Mutation in Locally Advanced Papillary Thyroid Cancer
by Woo Kyung Lee, Seul Gi Lee, Seung Hyuk Yim, Daham Kim, Hyunji Kim, Seonhyang Jeong, Sang Geun Jung, Young Suk Jo and Jandee Lee
Int. J. Mol. Sci. 2018, 19(10), 2867; https://doi.org/10.3390/ijms19102867 - 21 Sep 2018
Cited by 10 | Viewed by 4327
Abstract
Locally advanced thyroid cancer exhibits aggressive clinical features requiring extensive neck dissection. Therefore, it is important to identify changes in the tumor biology before local progression. Here, whole exome sequencing (WES) using tissues from locally advanced papillary thyroid cancer (PTC) presented a large [...] Read more.
Locally advanced thyroid cancer exhibits aggressive clinical features requiring extensive neck dissection. Therefore, it is important to identify changes in the tumor biology before local progression. Here, whole exome sequencing (WES) using tissues from locally advanced papillary thyroid cancer (PTC) presented a large number of single nucleotide variants (SNVs) in the metastatic lymph node (MLN), but not in normal tissues and primary tumors. Among those MLN-specific SNVs, a novel HHIP G516R (G1546A) mutation was also observed. Interestingly, in-depth analysis for exome sequencing data from the primary tumor presented altered nucleotide ‘A’ at a very low frequency indicating intra-tumor heterogeneity between the primary tumor and MLN. Computational prediction models such as PROVEAN and Polyphen suggested that HHIP G516R might affect protein function and stability. In vitro, HHIP G516R increased cell proliferation and promoted cell migration in thyroid cancer cells. HHIP G516R, a missense mutation, could be a representative example for the intra-tumor heterogeneity of locally advanced thyroid cancer, which can be a potential future therapeutic target for this disease. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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14 pages, 1509 KiB  
Article
Coexistence of TERT Promoter Mutations and the BRAF V600E Alteration and Its Impact on Histopathological Features of Papillary Thyroid Carcinoma in a Selected Series of Polish Patients
by Dagmara Rusinek, Aleksandra Pfeifer, Jolanta Krajewska, Malgorzata Oczko-Wojciechowska, Daria Handkiewicz-Junak, Agnieszka Pawlaczek, Jadwiga Zebracka-Gala, Malgorzata Kowalska, Renata Cyplinska, Ewa Zembala-Nozynska, Mykola Chekan, Ewa Chmielik, Aleksandra Kropinska, Roman Lamch, Beata Jurecka-Lubieniecka, Barbara Jarzab and Agnieszka Czarniecka
Int. J. Mol. Sci. 2018, 19(9), 2647; https://doi.org/10.3390/ijms19092647 - 06 Sep 2018
Cited by 26 | Viewed by 3878
Abstract
TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence [...] Read more.
TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of TERTp mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the BRAF V600E mutation. A total of 189 consecutive PTC specimens with known BRAF mutational status were evaluated. TERTp mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional TERTp alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the TERTp hotspot mutations were highly correlated with the presence of the BRAF V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of TERTp mutations being key molecular modulators responsible for PTC aggressiveness requires further studies. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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15 pages, 5260 KiB  
Article
Heme Oxygenase-1 Inhibitors Induce Cell Cycle Arrest and Suppress Tumor Growth in Thyroid Cancer Cells
by Po-Sheng Yang, Yi-Chiung Hsu, Jie-Jen Lee, Ming-Jen Chen, Shih-Yuan Huang and Shih-Ping Cheng
Int. J. Mol. Sci. 2018, 19(9), 2502; https://doi.org/10.3390/ijms19092502 - 24 Aug 2018
Cited by 28 | Viewed by 4199
Abstract
Heme oxygenase-1 (HO-1) is induced by a variety of stimuli and plays a multifaceted role in cellular protection. We have shown that HO-1 is overexpressed in thyroid cancer and is associated with tumor aggressiveness. Therefore, we set out to assess the effects of [...] Read more.
Heme oxygenase-1 (HO-1) is induced by a variety of stimuli and plays a multifaceted role in cellular protection. We have shown that HO-1 is overexpressed in thyroid cancer and is associated with tumor aggressiveness. Therefore, we set out to assess the effects of HO-1 inhibitors on the biology of thyroid cancer cells. Two different classes of HO-1 inhibitors were used, including a metalloporphyrin, zinc protoporphyrin-IX (ZnPP), and an azole antifungal agent, ketoconazole. The viability and colony formation of thyroid cancer cells decreased in a concentration- and time-dependent fashion following treatment with HO-1 inhibitors. Cancer cells exhibited a higher sensitivity to HO-1 inhibitors than non-malignant cells. HO-1 inhibitors induced a G0/G1 arrest accompanied by decreased cyclin D1 and CDK4 expressions and an increase in levels of p21 and p27. HO-1 inhibitors significantly increased intracellular ROS levels and suppressed cell migration and invasion. Oxygen consumption rate and mitochondrial mass were increased with ZnPP treatment. Mice treated with ZnPP had a reduced xenograft growth and diminished cyclin D1 and Ki-67 staining in tumor sections. Taken together, HO-1 inhibitors might have therapeutic potential for inducing cell cycle arrest and promoting growth suppression of thyroid cancer cells in vitro and in vivo. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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16 pages, 4502 KiB  
Article
Semantic Analysis of Posttranslational Modification of Proteins Accumulated in Thyroid Cancer Cells Exposed to Simulated Microgravity
by Johann Bauer, Markus Wehland, Manfred Infanger, Daniela Grimm and Erich Gombocz
Int. J. Mol. Sci. 2018, 19(8), 2257; https://doi.org/10.3390/ijms19082257 - 01 Aug 2018
Cited by 25 | Viewed by 4424
Abstract
When monolayers of tissue cancer cells of various origins are exposed to real or simulated microgravity, many cells leave the monolayer and assemble to three-dimensional (3D) aggregates (spheroids). In order to define the cellular machinery leading to this change in growth behavior of [...] Read more.
When monolayers of tissue cancer cells of various origins are exposed to real or simulated microgravity, many cells leave the monolayer and assemble to three-dimensional (3D) aggregates (spheroids). In order to define the cellular machinery leading to this change in growth behavior of FTC-133 human thyroid cancer cells and MCF-7 breast cancer cells, we recently performed proteome analyses on these cell lines and determined the proteins’ accumulation in monolayer cells grown under 1g-conditions as well as in the cells of spheroids assembled under simulated microgravity during three and 14 days, respectively. At that time, an influence of the increment or decrement of some of the more than 5000 proteins detected in each cell line was investigated. In this study, we focused on posttranslational modifications (PTMs) of proteins. For this purpose, we selected candidates from the list of the proteins detected in the two preceding proteome analyses, which showed significant accumulation in spheroid cells as compared to 1g monolayer cells. Then we searched for those PTMs of the selected proteins, which according to the literature have already been determined experimentally. Using the Semantic Protocol and RDF Query Language (SPARQL), various databases were examined. Most efficient was the search in the latest version of the dbPTM database. In total, we found 72 different classes of PTMs comprising mainly phosphorylation, glycosylation, ubiquitination and acetylation. Most interestingly, in 35 of the 69 proteins, N6 residues of lysine are modifiable. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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15 pages, 2647 KiB  
Article
Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs
by Sabine Wächter, Annette Wunderlich, Brandon H. Greene, Silvia Roth, Moritz Elxnat, Sebastian A. Fellinger, Frederik A. Verburg, Markus Luster, Detlef K. Bartsch and Pietro Di Fazio
Int. J. Mol. Sci. 2018, 19(7), 2077; https://doi.org/10.3390/ijms19072077 - 17 Jul 2018
Cited by 19 | Viewed by 3970
Abstract
Background: The MEK (mitogen-activated protein kinase)–inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS; [...] Read more.
Background: The MEK (mitogen-activated protein kinase)–inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS; SLC5A5) and associated miRNAs in thyroid cancer cells. Methods: Cytotoxicity was assessed by viability assay in TPC1, BCPAP, C643 and 8505C thyroid cancer cell lines. NIS, hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b-3p expression was determined by quantitative RT-PCR. NIS protein was detected by Western blot. Radioiodine uptake was performed with a Gamma counter. Results: Selumetinib caused a significant reduction of cell viability in all thyroid cancer cell lines. NIS transcript was restored by selumetinib in all cell lines. Its protein level was found up-regulated in TPC1 and BCPAP cells and down-regulated in C643 and 8505C cells after treatment with selumetinib. Treatment with selumetinib caused a down-regulation of hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p in TPC1 and BCPAP cells. In 8505C cells, a stable or down-regulated hsa-miR-146b-5p was detected after 1h and 48h of treatment. C643 cells showed stable or up-regulated hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p. Selumetinib treatment caused an increase of radioiodine uptake, which was significant in TPC1 cells. Conclusions: The study shows for the first time that selumetinib restores NIS by the inhibition of its related targeting miRNAs. Further studies are needed to clarify the exact mechanism activated by hsa-miR-146b-5p, hsa-miR-146b-3p and hsa-let7f-5p to stabilise NIS. Restoration of NIS could represent a milestone for the treatment of advanced RR-DTC. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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13 pages, 1204 KiB  
Article
A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model
by Wen-Bin Zhong, Yuan-Chin Tsai, Li-Han Chin, Jen-Ho Tseng, Li-Wen Tang, Steve Horng, Yu-Ching Fan and Sung-Po Hsu
Int. J. Mol. Sci. 2018, 19(7), 1834; https://doi.org/10.3390/ijms19071834 - 22 Jun 2018
Cited by 24 | Viewed by 4519
Abstract
Anaplastic thyroid cancer (ATC) is a malignant subtype of thyroid cancers and its mechanism of development remains inconclusive. Importantly, there is no effective strategy for treatment since ATC is not responsive to conventional therapies, including radioactive iodine therapy and thyroid-stimulating hormone suppression. Here, [...] Read more.
Anaplastic thyroid cancer (ATC) is a malignant subtype of thyroid cancers and its mechanism of development remains inconclusive. Importantly, there is no effective strategy for treatment since ATC is not responsive to conventional therapies, including radioactive iodine therapy and thyroid-stimulating hormone suppression. Here, we report that a combinational approach consisting of drugs designed for targeting lipid metabolism, lovastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR) and troglitazone (an agonist of peroxisome proliferator-activated receptor gamma, PPARγ), exhibits anti-proliferation in cell culture systems and leads to tumor regression in a mouse xenograft model. The composition contains a sub-lethal concentration of both drugs and exhibits low toxicity to certain types of normal cells. Our results support a hypothesis that the inhibitory effect of the combination is partly through a cell cycle arrest at G0/G1 phase, as evidenced by the induction of cyclin-dependent kinase inhibitors, p21cip and p27kip, and the reduction of hyperphosphorylated retinoblastoma protein (pp-Rb)-E2F1 signaling. Therefore, targeting two pathways involved in lipid metabolism may provide a new direction for treating ATC. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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17 pages, 2565 KiB  
Article
Differences in the Plasma Proteome of Patients with Hypothyroidism before and after Thyroid Hormone Replacement: A Proteomic Analysis
by Assim A. Alfadda, Hicham Benabdelkamel, Afshan Masood, Anwar A. Jammah and Aishah A. Ekhzaimy
Int. J. Mol. Sci. 2018, 19(1), 88; https://doi.org/10.3390/ijms19010088 - 01 Jan 2018
Cited by 34 | Viewed by 4992
Abstract
Thyroid hormone is a potent stimulator of metabolism, playing a critical role in regulating energy expenditure and in key physiological mechanisms, such as growth and development. Although administration of thyroid hormone in the form of levo thyroxine (l-thyroxine) has been used [...] Read more.
Thyroid hormone is a potent stimulator of metabolism, playing a critical role in regulating energy expenditure and in key physiological mechanisms, such as growth and development. Although administration of thyroid hormone in the form of levo thyroxine (l-thyroxine) has been used to treat hypothyroidism for many years, the precise molecular basis of its physiological actions remains uncertain. Our objective was to define the changes in circulating protein levels that characterize alterations in thyroid hormone status. To do this, an integrated untargeted proteomic approach with network analysis was used. This study included 10 age-matched subjects with newly diagnosed overt hypothyroidism. Blood was collected from subjects at baseline and at intervals post-treatment with l-thyroxine until they reached to euthyroid levels. Plasma protein levels were compared by two-dimensional difference in gel electrophoresis (2D-DIGE) pre- and post-treatment. Twenty differentially expressed protein spots were detected. Thirteen were identified, and were found to be unique protein sequences by MALDI-TOF mass spectrometry. Ten proteins were more abundant in the hypothyroid vs. euthyroid state: complement C2, serotransferrin, complement C3, Ig κ chain C region, α-1-antichymotrypsin, complement C4-A, haptoglobin, fibrinogen α chain, apolipoprotein A-I, and Ig α-1 chain C region. Three proteins were decreased in abundance in the hypothyroid vs. euthyroid state: complement factor H, paraneoplastic antigen-like protein 6A, and α-2-macroglobulin. The differentially abundant proteins were investigated by Ingenuity Pathway Analysis (IPA) to reveal their associations with known biological functions. Their connectivity map included interleukin-6 (IL-6) and tumour necrosis factor α (TNF-α) as central nodes and the pathway identified with the highest score was involved in neurological disease, psychological disorders, and cellular movement. The comparison of the plasma proteome between the hypothyroid vs euthyroid states revealed differences in the abundance of proteins involved in regulating the acute phase response. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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8585 KiB  
Article
Simvastatin Inhibits Cell Proliferation and Migration in Human Anaplastic Thyroid Cancer
by Mei-Chieh Chen, Yuan-Chin Tsai, Jen-Ho Tseng, Jr-Jiun Liou, Steve Horng, Heng-Ching Wen, Yu-Ching Fan, Wen-Bin Zhong and Sung-Po Hsu
Int. J. Mol. Sci. 2017, 18(12), 2690; https://doi.org/10.3390/ijms18122690 - 13 Dec 2017
Cited by 20 | Viewed by 4426
Abstract
Malignant human anaplastic thyroid cancer (ATC) is pertinacious to conventional therapies. The present study investigated the anti-cancer activity of simvastatin and its underlying regulatory mechanism in cultured ATC cells. Simvastatin (0–20 μM) concentration-dependently reduced cell viability and relative colony formation. Depletions of mevalonate [...] Read more.
Malignant human anaplastic thyroid cancer (ATC) is pertinacious to conventional therapies. The present study investigated the anti-cancer activity of simvastatin and its underlying regulatory mechanism in cultured ATC cells. Simvastatin (0–20 μM) concentration-dependently reduced cell viability and relative colony formation. Depletions of mevalonate (MEV) and geranylgeranyl pyrophosphate (GGpp) by simvastatin induced G1 arrest and increased apoptotic cell populations at the sub-G1 phase. Adding MEV and GGpp prevented the simvastatin-inhibited cell proliferation. Immunoblotting analysis illustrated that simvastatin diminished the activation of RhoA and Rac1 protein, and this effect was prevented by pre-treatment with MEV and GGpp. Simvastatin increased the levels of p21cip and p27kip proteins and reduced the levels of hyperphosphorylated-Rb, E2F1 and CCND1 proteins. Adding GGpp abolished the simvastatin-increased levels of p27kip protein, and the GGpp-caused effect was abolished by Skp2 inhibition. Introduction of Cyr61 siRNA into ATC cells prevented the epidermal growth factor (EGF)-enhanced cell migration. The EGF-induced increases of Cyr61 protein expression and cell migration were prevented by simvastatin. Taken together, these results suggest that simvastatin induced ATC proliferation inhibition through the deactivation of RhoA/Rac1 protein and overexpression of p21cip and p27kip, and migration inhibition through the abrogation of Cyr61 protein expression. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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21 pages, 3953 KiB  
Review
Fighting Thyroid Cancer with Microgravity Research
by Marcus Krüger, Daniela Melnik, Sascha Kopp, Christoph Buken, Jayashree Sahana, Johann Bauer, Markus Wehland, Ruth Hemmersbach, Thomas J. Corydon, Manfred Infanger and Daniela Grimm
Int. J. Mol. Sci. 2019, 20(10), 2553; https://doi.org/10.3390/ijms20102553 - 24 May 2019
Cited by 34 | Viewed by 6280
Abstract
Microgravity in space or simulated by special ground-based devices provides an unusual but unique environment to study and influence tumour cell processes. By investigating thyroid cancer cells in microgravity for nearly 20 years, researchers got insights into tumour biology that had not been [...] Read more.
Microgravity in space or simulated by special ground-based devices provides an unusual but unique environment to study and influence tumour cell processes. By investigating thyroid cancer cells in microgravity for nearly 20 years, researchers got insights into tumour biology that had not been possible under normal laboratory conditions: adherently growing cancer cells detach from their surface and form three-dimensional structures. The cells included in these multicellular spheroids (MCS) were not only altered but behave also differently to those grown in flat sheets in normal gravity, more closely mimicking the conditions in the human body. Therefore, MCS became an invaluable model for studying metastasis and developing new cancer treatment strategies via drug targeting. Microgravity intervenes deeply in processes such as apoptosis and in structural changes involving the cytoskeleton and the extracellular matrix, which influence cell growth. Most interestingly, follicular thyroid cancer cells grown under microgravity conditions were shifted towards a less-malignant phenotype. Results from microgravity research can be used to rethink conventional cancer research and may help to pinpoint the cellular changes that cause cancer. This in turn could lead to novel therapies that will enhance the quality of life for patients or potentially develop new preventive countermeasures. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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15 pages, 1596 KiB  
Review
Pazopanib, Cabozantinib, and Vandetanib in the Treatment of Progressive Medullary Thyroid Cancer with a Special Focus on the Adverse Effects on Hypertension
by Rikke Vilsbøll Milling, Daniela Grimm, Marcus Krüger, Jirka Grosse, Sascha Kopp, Johann Bauer, Manfred Infanger and Markus Wehland
Int. J. Mol. Sci. 2018, 19(10), 3258; https://doi.org/10.3390/ijms19103258 - 20 Oct 2018
Cited by 32 | Viewed by 9260
Abstract
Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form [...] Read more.
Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form of cancer is often insensitive to conventional chemotherapy, but the use of tyrosine kinase inhibitors (TKIs), such as pazopanib, cabozantinib, and vandetanib, has shown promising results with an increase in progression-free survival and prolonged lifetime. Therefore, we focused on the pharmacological characteristics of TKIs, their mechanism of action, their application as a secondary treatment option for MTC, their efficacy as a cancer drug treatment, and reviewed the ongoing clinical trials. TKIs also act systemically causing various adverse events (AEs). One common AE of this treatment is hypertension, known to be associated with cardiovascular disease and can therefore potentially worsen the well-being of the treated patients. The available treatment strategies of drug-induced hypertension were discussed. The mechanism behind the development of hypertension is still unclear. Therefore, the treatment of this AE remains symptomatic. Thus, future studies are necessary to investigate the link between tumor growth inhibition and hypertension. In addition, optimized, individual treatment strategies should be implemented. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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24 pages, 1756 KiB  
Review
Glycosylation in the Thyroid Gland: Vital Aspects of Glycoprotein Function in Thyrocyte Physiology and Thyroid Disorders
by Marta Ząbczyńska, Kamila Kozłowska and Ewa Pocheć
Int. J. Mol. Sci. 2018, 19(9), 2792; https://doi.org/10.3390/ijms19092792 - 17 Sep 2018
Cited by 37 | Viewed by 8395
Abstract
The key proteins responsible for hormone synthesis in the thyroid are glycosylated. Oligosaccharides strongly affect the function of glycosylated proteins. Both thyroid-stimulating hormone (TSH) secreted by the pituitary gland and TSH receptors on the surface of thyrocytes contain N-glycans, which are crucial [...] Read more.
The key proteins responsible for hormone synthesis in the thyroid are glycosylated. Oligosaccharides strongly affect the function of glycosylated proteins. Both thyroid-stimulating hormone (TSH) secreted by the pituitary gland and TSH receptors on the surface of thyrocytes contain N-glycans, which are crucial to their proper activity. Thyroglobulin (Tg), the protein backbone for synthesis of thyroid hormones, is a heavily N-glycosylated protein, containing 20 putative N-glycosylated sites. N-oligosaccharides play a role in Tg transport into the follicular lumen, where thyroid hormones are produced, and into thyrocytes, where hyposialylated Tg is degraded. N-glycans of the cell membrane transporters sodium/iodide symporter and pendrin are necessary for iodide transport. Some changes in glycosylation result in abnormal activity of the thyroid and alteration of the metabolic clearance rate of hormones. Alteration of glycan structures is a pathological process related to the progression of chronic diseases such as thyroid cancers and autoimmunity. Thyroid carcinogenesis is accompanied by changes in sialylation and fucosylation, β1,6-branching of glycans, the content and structure of poly-LacNAc chains, as well as O-GlcNAcylation, while in thyroid autoimmunity the main processes affected are sialylation and fucosylation. The glycobiology of the thyroid gland is an intensively studied field of research, providing new data helpful in understanding the role of the sugar component in thyroid protein biology and disorders. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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1854 KiB  
Review
Preclinical Imaging for the Study of Mouse Models of Thyroid Cancer
by Adelaide Greco, Luigi Auletta, Francesca Maria Orlandella, Paola Lucia Chiara Iervolino, Michele Klain, Giuliana Salvatore and Marcello Mancini
Int. J. Mol. Sci. 2017, 18(12), 2731; https://doi.org/10.3390/ijms18122731 - 16 Dec 2017
Cited by 6 | Viewed by 5458
Abstract
Thyroid cancer, which represents the most common tumors among endocrine malignancies, comprises a wide range of neoplasms with different clinical aggressiveness. One of the most important challenges in research is to identify mouse models that most closely resemble human pathology; other goals include [...] Read more.
Thyroid cancer, which represents the most common tumors among endocrine malignancies, comprises a wide range of neoplasms with different clinical aggressiveness. One of the most important challenges in research is to identify mouse models that most closely resemble human pathology; other goals include finding a way to detect markers of disease that common to humans and mice and to identify the most appropriate and least invasive therapeutic strategies for specific tumor types. Preclinical thyroid imaging includes a wide range of techniques that allow for morphological and functional characterization of thyroid disease as well as targeting and in most cases, this imaging allows quantitative analysis of the molecular pattern of the thyroid cancer. The aim of this review paper is to provide an overview of all of the imaging techniques used to date both for diagnosis and theranostic purposes in mouse models of thyroid cancer. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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338 KiB  
Review
Current Advances in Thyroid Cancer Management. Are We Ready for the Epidemic Rise of Diagnoses?
by Dagmara Rusinek, Ewa Chmielik, Jolanta Krajewska, Michal Jarzab, Malgorzata Oczko-Wojciechowska, Agnieszka Czarniecka and Barbara Jarzab
Int. J. Mol. Sci. 2017, 18(8), 1817; https://doi.org/10.3390/ijms18081817 - 22 Aug 2017
Cited by 33 | Viewed by 6624
Abstract
A rising incidence of thyroid cancers (TCs) mainly small tumors, observed during recent years, lead to many controversies regarding treatment strategies. TCs represent a distinct molecular background and clinical outcome. Although in most cases TCs are characterized by a good prognosis, there are [...] Read more.
A rising incidence of thyroid cancers (TCs) mainly small tumors, observed during recent years, lead to many controversies regarding treatment strategies. TCs represent a distinct molecular background and clinical outcome. Although in most cases TCs are characterized by a good prognosis, there are some aggressive forms, which do not respond to standard treatment. There are still some questions, which have to be resolved to avoid dangerous simplifications in the clinical management. In this article, we focused on the current advantages in preoperative molecular diagnostic tests and histopathological examination including noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). We discussed the controversies regarding the extent of thyroid surgery and adjuvant radioiodine therapy, as well as new treatment modalities for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Considering medullary thyroid cancer (MTC), we analyzed a clinical management based on histopathology and RET (ret proto-oncogene) mutation genotype, disease follow-up with a special attention to serum calcitonin doubling time as an important prognostic marker, and targeted therapy applied in advanced MTC. In addition, we provided some data regarding anaplastic thyroid cancer (ATC), a highly lethal neoplasm, which lead to death in nearly 100% of patients due to the lack of effective treatment options. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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