scholarly journals Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals

2021 ◽  
Vol 12 ◽  
Author(s):  
Fiorenza Gianì ◽  
Roberta Masto ◽  
Maria Antonietta Trovato ◽  
Annarita Franco ◽  
Giuseppe Pandini ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Thyroid Cancer ◽  
Response Curve ◽  
Living Cells ◽  
Human Thyroid ◽  
Target Cells ◽  
Volcanic Area ◽  
Thyroid Cells ◽  
Biphasic Pattern ◽  
Thyroid Cancer Incidence

Thyroid cancer incidence is markedly increased in volcanic areas where residents are biocontaminated by chronic lifelong exposure to slightly increased metals in the environment. Metals can influence the biology of living cells by a variety of mechanisms, depending not only on the dose and length of exposure but also on the type and stage of differentiation of target cells. We explored the effect of five heavy metals (Cu, Hg, Pd, W and Zn) at nanomolar concentrations (the biocontamination level in residents of the volcanic area in Sicily where thyroid cancer is increased) on stimulating the proliferation of undifferentiated (thyrospheres) and differentiated human thyroid cells. Thyrosphere proliferation was significantly increased after exposure to each individual metal and a greater stimulating effect was observed when a mixture of the examined metals was used. No effect was seen in differentiated thyrocytes. For all metals, the dose-response curve followed a biphasic pattern that is typical of hormesis. Thyrosphere growth concerned the size rather than number, except with the metal mixture. An altered morphology was also observed in metal-treated thyrospheres. Metal-induced proliferation was due to activation of the ERK1/2 pathway, as confirmed by growth inhibition when ERK1/2 signaling was blocked. These studies show that stem/precursor thyroid cells are sensitive to small increases in environmental metal concentrations that are harmless for differentiated thyrocytes.

scholarly journals Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny

2019 ◽  
Vol 26 (8) ◽  
pp. 713-725 ◽  
Author(s):  
Fiorenza Gianì ◽  
Giuseppe Pandini ◽  
Nunzio Massimo Scalisi ◽  
Paolo Vigneri ◽  
Carmine Fazzari ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Chronic Exposure ◽  
Low Dose ◽  
Biological Effects ◽  
Precursor Cells ◽  
Mount Etna ◽  
Human Thyroid ◽  
Volcanic Area ◽  
Thyroid Cells

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

scholarly journals Heavy Metals in the Environment and Thyroid Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4052
Author(s):  
Fiorenza Gianì ◽  
Roberta Masto ◽  
Maria Antonietta Trovato ◽  
Pasqualino Malandrino ◽  
Marco Russo ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Thyroid Cancer ◽  
Molecular Mechanisms ◽  
Human Thyroid ◽  
Thyroid Cells ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Low Levels ◽  
Causative Link

In recent decades, the incidence of thyroid cancer has increased more than most other cancers, paralleling the generalized worldwide increase in metal pollution. This review provides an overview of the evidence supporting a possible causative link between the increase in heavy metals in the environment and thyroid cancer. The major novelty is that human thyroid stem/progenitor cells (thyrospheres) chronically exposed to different metals at slightly increased environmentally relevant concentrations show a biphasic increase in proliferation typical of hormesis. The molecular mechanisms include, for all metals investigated, the activation of the extracellular signal-regulated kinase (ERK1/2) pathway. A metal mixture, at the same concentration of individual metals, was more effective. Under the same conditions, mature thyrocytes were unaffected. Preliminary data with tungsten indicate that, after chronic exposure, additional abnormalities may occur and persist in thyrocytes derived from exposed thyrospheres, leading to a progeny population of transformation-prone thyroid cells. In a rat model predisposed to develop thyroid cancer, long-term exposure to low levels of metals accelerated and worsened histological signs of malignancy in the thyroid. These studies provide new insight on metal toxicity and carcinogenicity occurring in thyroid cells at a low stage of differentiation when chronically exposed to metal concentrations that are slightly increased, albeit still in the “normal” range.

scholarly journals Increased Thyroid Cancer Incidence in Volcanic Areas: A Role of Increased Heavy Metals in the Environment?

2020 ◽  
Vol 21 (10) ◽  
pp. 3425 ◽  
Author(s):  
Pasqualino Malandrino ◽  
Marco Russo ◽  
Fiorenza Gianì ◽  
Gabriella Pellegriti ◽  
Paolo Vigneri ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Thyroid Cancer ◽  
Cancer Incidence ◽  
Biological Effects ◽  
Anthropogenic Pollution ◽  
Volcanic Area ◽  
Carcinogenic Effect ◽  
Metal Levels ◽  
Intracellular Binding ◽  
Thyroid Cancer Incidence

Thyroid cancer incidence is significantly increased in volcanic areas, where relevant non-anthropogenic pollution with heavy metals is present in the environment. This review will discuss whether chronic lifelong exposure to slightly increased levels of metals can contribute to the increase in thyroid cancer in the residents of a volcanic area. The influence of metals on living cells depends on the physicochemical properties of the metals and their interaction with the target cell metallostasis network, which includes transporters, intracellular binding proteins, and metal-responsive elements. Very little is known about the carcinogenic potential of slightly increased metal levels on the thyroid, which might be more sensitive to mutagenic damage because of its unique biology related to iodine, which is a very reactive and strongly oxidizing agent. Different mechanisms could explain the specific carcinogenic effect of borderline/high environmental levels of metals on the thyroid, including (a) hormesis, the nonlinear response to chemicals causing important biological effects at low concentrations; (b) metal accumulation in the thyroid relative to other tissues; and (c) the specific effects of a mixture of different metals. Recent evidence related to all of these mechanisms is now available, and the data are compatible with a cause–effect relationship between increased metal levels in the environment and an increase in thyroid cancer incidence.

scholarly journals Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer

2013 ◽  
Vol 21 (2) ◽  
pp. 161-173 ◽  
Author(s):  
Zongjing Zhang ◽  
Dingxie Liu ◽  
Avaniyapuram Kannan Murugan ◽  
Zhimin Liu ◽  
Mingzhao Xing
Keyword(s):  
Thyroid Cancer ◽  
Histone Acetylation ◽  
Underlying Mechanism ◽  
Histone Deacetylation ◽  
Braf V600e ◽  
Epigenetic Mechanism ◽  
Human Thyroid ◽  
Sodium Iodide Symporter ◽  
Thyroid Cells ◽  
Rat Thyroid

The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the chromatin immunoprecipitation approach, we examined histone acetylation status on the lysine residues H3K9/14, H3K18, total H4, and H4K16 at the NIS promoter under the influence of BRAF V600E. We found that expression of stably or transiently transfected BRAF V600E inhibited NIS expression while the deacetylase inhibitor SAHA stimulated NIS expression in PCCL3 rat thyroid cells. Although BRAF V600E enhanced global histone acetylation, it caused histone deacetylation at the NIS promoter while SAHA caused acetylation in the cells. In human thyroid cancer BCPAP cells harboring homozygous BRAF V600E mutation, BRAF V600E inhibitor, PLX4032, and MEK inhibitor, AZD6244, increased histone acetylation of the NIS promoter, suggesting that BRAF V600E normally maintained histone in a deacetylated state at the NIS promoter. The regions most commonly affected with deacetylation by BRAF V600E were the transcriptionally active areas upstream of the translation start that contained important transcription factor binding sites, including nucleotides −297/−107 in the rat NIS promoter and −692/−370 in the human NIS promoter. Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer.

scholarly journals Transforming acidic coiled-coil 3 and Aurora-A interact in human thyrocytes and their expression is deregulated in thyroid cancer tissues

2007 ◽  
Vol 14 (3) ◽  
pp. 827-837 ◽  
Author(s):  
Salvatore Ulisse ◽  
Enke Baldini ◽  
Matteo Toller ◽  
Jean-Guy Delcros ◽  
Aurélie Guého ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Thyroid Cancer ◽  
Coiled Coil ◽  
Human Thyroid ◽  
Mrna Levels ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Thyroid Cells ◽  
Cancer Tissues

Aurora-A kinase has recently been shown to be deregulated in thyroid cancer cells and tissues. Among the Aurora-A substrates identified, transforming acidic coiled-coil (TACC3), a member of the TACC family, plays an important role in cell cycle progression and alterations of its expression occur in different cancer tissues. In this study, we demonstrated the expression of the TACC3 gene in normal human thyroid cells (HTU5), and its modulation at both mRNA and protein levels during cell cycle. Its expression was found, with respect to HTU5 cells, unchanged in cells derived from a benign thyroid follicular tumor (HTU42), and significantly reduced in cell lines derived from follicular (FTC-133), papillary (B-CPAP), and anaplastic thyroid carcinomas (CAL-62 and 8305C). Moreover, in 16 differentiated thyroid cancer tissues, TACC3 mRNA levels were found, with respect to normal matched tissues, reduced by twofold in 56% of cases and increased by twofold in 44% of cases. In the same tissues, a correlation between the expression of the TACC3 and Aurora-A mRNAs was observed. TACC3 and Aurora-A interact in vivo in thyroid cells and both proteins localized onto the mitotic structure of thyroid cells. Finally, TACC3 localization on spindle microtubule was no more observed following the inhibition of Aurora kinase activity by VX-680. We propose that Aurora-A and TACC3 interaction is important to control the mitotic spindle organization required for proper chromosome segregation.

scholarly journals Proliferative Activity of Human Thyroid Cells in Various Age Groups and Its Correlation with the Risk of Thyroid Cancer after Radiation Exposure

2006 ◽  
Vol 91 (7) ◽  
pp. 2672-2677 ◽  
Author(s):  
Ali G. Saad ◽  
Seena Kumar ◽  
Elaine Ron ◽  
Jay H. Lubin ◽  
Jerzy Stanek ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Proliferative Activity ◽  
Age Groups ◽  
Inverse Correlation ◽  
Immunohistochemical Analysis ◽  
Human Thyroid ◽  
Ki 67 ◽  
Thyroid Cells ◽  
Proliferative Rate

Abstract Context: The thyroid gland is vulnerable to the carcinogenic effects of ionizing radiation, and there is a well-documented inverse correlation between thyroid cancer and age at exposure, particularly for ages less than 20 yr. One of the factors responsible for this phenomenon may be more rapid cell proliferation in children. Objective: The objective of this study was to determine the proliferative rate of normal human thyroid cells in different age groups. Design: We used immunohistochemical analysis to determine the Ki-67 proliferative index in 117 thyroid glands obtained at autopsy, including 25 fetal thyroids (11–40 wk gestation), 55 childhood thyroids (0–19 yr), and 37 adult thyroids (20–60 yr). Results: The rate of Ki-67 labeling in the three groups was 7.4 ± 6.10, 0.23 ± 0.15, and 0.08 ± 0.04% respectively, demonstrating an overall trend for diminishing proliferative activity of thyroid cells with increasing age. However, a lack of correlation was noted between the slopes of cancer risk calculated from previous studies of irradiated populations and proliferative rate in the pediatric age intervals of 0–4 and 5–9 yr, suggesting that other factors are likely to be responsible for the particularly high sensitivity to radiation-induced thyroid cancer among the youngest children. Conclusions: Our findings of a general decrease in proliferative activity of thyroid cells with age may explain, at least in part, the higher risks of radiation-related thyroid cancer in children compared with adults. However, the variation in the rate of cell proliferation is unlikely to be responsible entirely for this phenomenon and other factors may also be involved.

scholarly journals Formation of carcinogenic chromosomal rearrangements in human thyroid cells after induction of double-strand DNA breaks by restriction endonucleases

2012 ◽  
Vol 19 (3) ◽  
pp. 271-281 ◽  
Author(s):  
Viktoria Evdokimova ◽  
Manoj Gandhi ◽  
Jayanagendra Rayapureddi ◽  
James R Stringer ◽  
Yuri E Nikiforov
Keyword(s):  
Thyroid Cancer ◽  
Chromosomal Rearrangements ◽  
Restriction Endonucleases ◽  
Human Thyroid ◽  
Fusion Partner ◽  
Dependent Manner ◽  
Dna Breaks ◽  
Thyroid Cells ◽  
Restriction Sites

Ionizing radiation (IR) exposure increases the risk of thyroid cancer and other cancer types. Chromosomal rearrangements, such asRET/PTC, are characteristic features of radiation-associated thyroid cancer and can be induced by radiationin vitro. IR causes double-strand breaks (DSBs), suggesting that such damage leads toRET/PTC, but the rearrangement mechanism has not been established. To study the mechanism, we explored the possibility of inducingRET/PTCby electroporation of restriction endonucleases (REs) into HTori-3 human thyroid cells. We used five REs, which induced DSB in a dose-dependent manner similar to that seen with IR. Although all but one RE caused DSB in one or more of the three genes involved inRET/PTC, rearrangement was detected only in cells electroporated with either PvuII (25 and 100 U) or StuI (100 and 250 U). The predominant rearrangement type wasRET/PTC3, which is characteristic of human thyroid cancer arising early after Chernobyl-related radioactive iodine exposure. Both enzymes that producedRET/PTChad restriction sites only in one of the two fusion partner genes. Moreover, the two enzymes that producedRET/PTChad restriction sites present in clusters, which was not the case for RE that failed to induceRET/PTC. In summary, we establish a model of DSB induction by RE and report for the first time the formation of carcinogenic chromosomal rearrangements, predominantlyRET/PTC3, as a result of DSB produced by RE. Our data also raise a possibility thatRET/PTCrearrangement can be initiated by a complex DSB that is induced in one of the fusion partner genes.

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