Hypothyroidism Enhances Tumor Invasiveness and Metastasis Development

Martínez-Iglesias, Olaia; García‐Silva, Susana; Regadera, Javier; Aranda, Ana

doi:10.1371/journal.pone.0006428

Cited by 82 publications

(76 citation statements)

References 49 publications

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“…It is noteworthy that hypothyroid mice showed higher levels of necrosis in their tumors than the other studied groups, despite having levels of angiogenesis similar to those observed in euthyroid animals. Similar results were obtained by Martínez-Iglesias et al (2009) demonstrating that the reduced tumor volume in hypothyroid hosts was correlated with a lower proliferation rate of the tumors, which was also accompanied by enlargement of the necrotic area …”

Section: Discussionsupporting

confidence: 86%

“…Thus, the heterogeneity of the analyzed studies precludes firm conclusions. Martínez-Iglesias et al (2009) showed that hypothyroidism resulted in a decreased rate of solid tumor growth, as well as an increase in the development and number of metastases, in murine xenograft models of human hepatocarcinoma and breast cancer. However, low levels of circulating THs, induced by stress, enhanced tumor progression in mice, an effect that was reversed following T 4 administration (Frick et al 2009a,b).…”

Section: Introductionmentioning

confidence: 99%

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Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis

Sterle¹,

Valli²,

Cayrol³

et al. 2014

Journal of Endocrinology

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We have shown in vitro that thyroid hormones (THs) regulate the balance between proliferation and apoptosis of T lymphoma cells. The effects of THs on tumor development have been studied, but the results are still controversial. Herein, we show the modulatory action of thyroid status on the in vivo growth of T lymphoma cells. For this purpose, euthyroid, hypothyroid, and hyperthyroid mice received inoculations of EL4 cells to allow the development of solid tumors. Tumors in the hyperthyroid animals exhibited a higher growth rate, as evidenced by the early appearance of palpable solid tumors and the increased tumor volume. These results are consistent with the rate of cell division determined by staining tumor cells with carboxyfluorescein succinimidyl ester. Additionally, hyperthyroid mice exhibited reduced survival. Hypothyroid mice did not differ significantly from the euthyroid controls with respect to these parameters. Additionally, only tumors from hyperthyroid animals had increased expression levels of proliferating cell nuclear antigen and active caspase 3. Differential expression of cell cycle regulatory proteins was also observed. The levels of cyclins D1 and D3 were augmented in the tumors of the hyperthyroid animals, whereas the cell cycle inhibitors p16/INK4A (CDKN2A) and p27/Kip1 (CDKN1B) and the tumor suppressor p53 (TRP53) were increased in hypothyroid mice. Intratumoral and peritumoral vasculogenesis was increased only in hyperthyroid mice. Therefore, we propose that the thyroid status modulates the in vivo growth of EL4 T lymphoma through the regulation of cyclin, cyclin-dependent kinase inhibitor, and tumor suppressor gene expression, as well as the stimulation of angiogenesis.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis

Sterle¹,

Valli²,

Cayrol³

et al. 2014

Journal of Endocrinology

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“…Group A (euthyroid) was a control with normal drinking water. Group B (hypothyroid) was treated with 0.02% methymazole and 0.1% sodium perchlorate in the drinking water to repress T 3 synthesis (42). Additionally, Group C (hyperthyroid) was added T 3 in the drinking water (2 mg/L) (Sigma Chem.…”

Section: Establishing a Huh7 Cell Line Stably Overexpressing Pai-1-thementioning

confidence: 99%

Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC)-based Quantitative Proteomics Study of a Thyroid Hormone-regulated Secretome in Human Hepatoma Cells

Chen

Chi

et al. 2012

Molecular & Cellular Proteomics

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The thyroid hormone, 3, 3,5-triiodo-L-thyronine (T 3 ), regulates cell growth, development, differentiation, and metabolism via interactions with thyroid hormone receptors (TRs). However, the secreted proteins that are regulated by T 3 are yet to be characterized. In this study, we used the quantitative proteomic approach of stable isotope labeling with amino acids in cell culture coupled with nano-liquid chromatography-tandem MS performed on a LTQ-Orbitrap instrument to identify and characterize the T 3 -regulated proteins secreted in human hepatocellular carcinoma cell lines overexpressing TR␣1 (HepG2-TR␣1). In total, 1742 and 1714 proteins were identified and quantified, respectively, in three independent experiments. Among these, 61 up-regulated twofold and 11 down-regulated twofold proteins were identified. Eight proteins displaying increased expression and one with decreased expression in conditioned media were validated using

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“…ϩ/ϩ /TR␤ ϩ/ϩ animals with the same background were genotyped (11) and used for the studies. Wild-type mice were made hypothyroid (hT) by treatment with 0.02% methymazole and 0.1% sodium perchlorate in the drinking water (35). Treatment started when animals were 1 month old and was continued for 4 months.…”

mentioning

confidence: 99%

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Contreras‐Jurado

García-Serrano

Gómez-Ferrerı́a

et al. 2011

Journal of Biological Chemistry

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The actions of thyroid hormones are mediated by binding to nuclear receptors, TR␣ 4 and TR␤, that act as ligand-dependent transcription factors by association, generally as heterodimers with retinoid X receptors, with thyroid hormone response elements located in regulatory regions of target genes (1). TRs can also modulate expression of genes that do not contain a hormone response element by modulating the activity of other transcription factors and signaling pathways (2), including activator protein-1 (AP-1)-, cyclic AMP-response element-, and nuclear factor-B (NF-B)-dependent pathways (3-7).Studies with knock-out (KO) mice for TRs obtained by homologous recombination have indicated that KO mice for ␣1 and ␤ TR isoforms have different phenotypes (8 -10) and that the double KO mice, surprisingly, survive (11), indicating that these receptors are not required for viability. Although these animals show extreme resistance to thyroid hormones, they exhibit a milder phenotype than hypothyroid mice, indicating divergent consequences for hormone versus receptor deficiency for some actions.Although the skin is a target tissue for thyroid hormone action, no studies on the skin phenotype in TR KO mice have been reported. TR␣ and TR␤ mRNAs are present in the skin (12-15), and these receptors can regulate either positively or negatively the expression of selected keratins in cultured cells (16 -19). Clinical evidence (19 -27) as well as studies in hypothyroid mice and rats (28 -30) also suggest that thyroid hormones could be involved in epidermal proliferation and differentiation, hair growth, and wound healing besides affecting the function of dermal fibroblasts. A question emerging from these studies is how to distinguish between effects due to altered thyroid hormone levels and effects due to expression of specific TR isoforms.The TR KO mice represent an excellent model for the analysis of the role of these receptors in the skin and its response to hyperproliferative stimuli. Topical application of 12-O-tetradecanolyphorbol-13-acetate (TPA) to mouse skin is a well known model for induction of skin hyperproliferation and also promotes a strong inflammatory reaction that activates multiple immunostimulatory pathways. The skin response to TPA is associated with activation of several intracellular pathways (e.g. mitogen-activated protein kinases (MAPKs), AKT, NF-B, STAT3, and AP-1) as well as an increase in the content of chemical mediators, such as cytokines, chemokines, vasoactive peptides, prostaglandins, leukotrienes, and nitric oxide among others (31)(32)(33)(34).In this work, we have investigated skin proliferation and inflammation, before and after TPA application, in mice lacking TR␣1, TR␤, or both genes, comparing these responses with those of hypothyroid animals to distinguish the specific contributions of receptor expression and activation. We found that TRs and thyroid hormones are required for skin homeostasis after TPA treatment and that both receptor genes contribute to

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Hypothyroidism Enhances Tumor Invasiveness and Metastasis Development

Cited by 82 publications

References 49 publications

Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis

Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis

Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC)-based Quantitative Proteomics Study of a Thyroid Hormone-regulated Secretome in Human Hepatoma Cells

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

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