Selenium, selenoproteins and cancer of the thyroid

1 This is an Accepted Manuscript of an article published by Elsevier GmbH - Urban 1 und Fischer in Journal of Trace Elements in Medicine and Biology on Epub 2022 2 Diciembre available at: DOI: 10.1016/j.jtemb.2022.127115 3 4 5 6 Selenium, selenoproteins and cancer of the thyroid 7 8 Rui Manuel Rua a*, Fátima Nogales b, Olimpia Carreras b, María Luisa Ojeda b 9 10 a Faculty of Health Sciences, University Fernando Pessoa, 4249-004 Porto, Portugal; 11 [email protected] 12 b Department of Physiology, Faculty of Pharmacy, Seville University, 41012 Seville, 13 Spain; [email protected] (F.N); [email protected] (O.C.); [email protected] (M.L.O) 14 15 *Correspondence: [email protected] Tel.: +35122 -507-46 30 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Abstract: Selenium is an essential mineral element with important biological functions 32 for the whole body through incorporation into selenoproteins. This element is highly 33 concentrated in the thyroid gland. Selenoproteins provide antioxidant protection for this 34 tissue against the oxidative stress caused by free radicals and contribute, via 35 iodothyronine deiodinases, to the metabolism of thyroid hormones. It is known that 36 oxidative stress plays a major role in carcinogenesis and that in recent decades there has 37 been an increase in the incidence of thyroid cancer. The anti-carcinogenic action of 38 selenium, although not fully understood, is mainly attributable to selenoproteins 39 antioxidant properties, and to the ability to modulate cell proliferation (cell cycle and 40 apoptosis), energy metabolism, and cellular immune response, significantly altered 41 2 during tumorigenesis. Researchers have suggested that different forms of selenium 42 supplementation may be beneficial in the prevention and treatment of thyroid cancer; 43 however, the studies have several methodological limitations. This review is a summary 44 of the current knowledge on how selenium and selenoproteins related to thyroid cancer. 45 Keywords: selenium; selenoproteins; thyroid cancer; oxidative stress; supplementation 46 47 1. Introduction 48 Selenium (Se) is a critical microelement that was discovered and isolated for the first 49 time in 1817 by Swedish chemist Jöns Jacob Berzelius [1]. While not an essential 50 nutrient for plants, it is an essential nutrient for humans and many other life forms [2, 51 3]. In tissues, Se forms part of the amino acids selenomethionine and selenocysteine, 52 with the latter being responsible for the main known biological activity of 53 selenoproteins [4]. 54 The thyroid gland is the organ in the human body with the highest Se content per unit of 55 tissue [5,6]. In it, selenoproteins play a crucial role in the cellular defence system 56 against hydrogen peroxide (H2O2) and other reactive oxygen species (ROS) [7,8]. The 57 overproduction of free radicals, which triggers oxidative stress (OS), has been 58 associated with several diseases and with cancer in particular [9-11]. 59 Thyroid cancer is the most prevalent malignant neoplasm of the endocrine system and 60 its incidence has increased worldwide over the last four decades [12]. Histologically, 61 there are three main types of thyroid cancer: differentiated thyroid carcinoma, anaplastic 62 thyroid carcinoma and medullary thyroid carcinoma. Differentiated thyroid carcinoma 63 accounts for about 95% of thyroid cancers and it originates from follicular thyroid cells, 64 which are responsible for hormone production. This cancer can be subdivided into 65 papillary, follicular and Hurthle cell carcinoma. The first of these is the most common 66 and has the best prognosis [13]. Papillary thyroid cancer invades the lymph nodes, 67 spreading to the cervical lymph nodes and also, less frequently, to other distant sites 68 such as the lungs [14]. This pattern of dissemination is important and can be a 69 presenting symptom of papillary carcinoma because the primary tumour is very small in 70 some cases. When they are less than 1 cm they are often referred to as microcarcinomas 71 [15]. Conversely, in the follicular form, haematogenous metastases are more frequent, 72 mainly affecting the lungs and bones [14]. Hurthle cell carcinoma is follicular in origin, 73 with at least 75% of the cells being Hurthle cells and having capsular and/or vascular 74 invasion [16]. The Hurthle cell is characterized cytologically as a large cell with 75 abundant eosinophilic, granular cytoplasm, and a large hyperchromatic nucleus with a 76 prominent nucleolus. Cytoplasmic granularity is due to the presence of numerous 77 mitochondria [17]. Hurthle cell carcinoma is poorly avid to radioiodine and poorly 78 responsive to chemotherapy and radiation [18]. Hurthle cell carcinoma is believed to be 79 more aggressive than common follicular carcinoma [16]. 80 Since the thyroid is specially high in Se, and it plays an important role in this gland, the 81 relationship of Se with the incidence of thyroid cancer has been extensively studied 82 [11,19,20, 21, 22]. Thus, this review primarily aims to outline the current knowledge on 83 the association between Se, selenoproteins and thyroid cancer. 84 3 2. Selenium, selenoproteins and thyroid homeostasis 85 Adequate Se nutrition supports the synthesis and metabolism of thyroids hormones 86 (THs) and protects the thyroid gland from damage from overexposure to iodide which 87 increases OS [23]. Se is thus considered to be the second most important element in 88 thyroid metabolism after iodine, which plays a beneficial role by forming part of 89 different antioxidant selenoproteins [19]. 90 There are 25 different selenoproteins in the human body with at least one selenocysteine 91 (Sec) amino acid in their structure [24,25]. Their difference in Sec incorporation 92 efficiency leads to a “selenoprotein hierarchy” under selenium deficiency: proteins with 93 higher Sec incorporation efficiency exploit more charged Sec-specific (Sec-tRNASec ) 94 and are more rapidly synthesized [26]. The well-studied selenoproteins have antioxidant 95 properties (such as the glutathione peroxidase (GPx) family), are involved in redox 96 regulation (such as the thioredoxin reductases (TXNRD) family), or transport the serum 97 Se to tissues as selenoprotein P (SELENOP). But they also have other biological 98 functions, being regulators of growth, development, and cell differentiation, quality 99 control of protein biosynthesis, inhibitors of non-specific immune responses, 100 neutralizers of inflammatory responses, or antiapoptotic function [25, 27]. Many of 101 these selenoproteins are expressed in the thyroid gland and are involved in different 102 processes, such as the formation and regulation of THs (the iodothyronine deiodinases 103 (DIO) family) and redox processes linked to gland protection (GPx and TXNRD) (GPx 104 and TXNRD) [24]. These selenoproteins are necessary for the correct functioning of the 105 thyrotropin-releasing hormone (TRH) and thyroid stimulating hormone (TSH). TSH is 106 the major regulator of THs biosynthesis, since it activates a complex signaling network 107 across the TSH-receptor in thyrocytes and ends up forming T3 and T4 hormones 108 (Figure 1) [28]. In addition, TSH is involved in the selenoproteins regulation since, 109 through its receptor, it clearly increases the expression of GPx1, GPx3 and 110 TXNRD1[29]. This signaling pathway also stimulate the expression of DIO1 (and DIO2 111 in human) inside the thyrocytes as well as H2O2 production [29,30,31]. 112 THs mediate important physiological processes such as development, growth, 113 thermogenesis, and energy metabolism, as well as regulate fatty acid, cholesterol, and 114 carbohydrate homeostasis [32,33]. The synthesis of THs is a complex, multistep process 115 that encompasses several redox reactions that need H2O2 as an oxidative agent. THs 116 synthesis requires the oxidative iodination of specific tyrosine residues of thyroglobulin. 117 This process is catalyzed by the enzyme thyroid peroxidase (TPO), which requires an 118 appropriate amount of H2O2 for oxidation in the colloid (Figure 1). Therefore THs 119 synthesis needs H2O2 production. However, this is a disadvantage for thyrocyte, as this 120 large amount of H2O2 in the colloid could cross the apical membrane of the thyrocyte 121 and accumulate inside the cell, leading to OS-damage. 122 As it was mentioned, GPxs protect thyroid follicles from excess H2O2 that is produced 123 during the synthesis of THs [34]. Cytotoxic ROS are mainly produced in thyroid 124 follicles following activation of TPO as a result of the interaction between H2O2, iodide 125 and heme iron [35]. It has been demonstrated that the role of these selenoproteins, in 126 relation to H2O2, is fundamental to the thyroid, since in severe Se deficiency the lack of 127 GPx activity causes oxidative damage to the thyroid gland, leading to thyroid damage 128 4 and fibrosis [36, 37]. It has also been shown that pre-incubation of human thyroid 129 follicles with Se (sodium selenite), even at low doses (10 nM) increases GPx activity 130 and decreases cell death induced by high doses of H2O2, iodide or TGF-β [38, 39]. 131 The TXNRDs also play an important role in thyroid metabolism and, together with 132 thioredoxin (Trx) and NADPH, form the thioredoxin system, common to nearly all 133 living cells [40]. This system functions in thiol-dependent thiol-disulfide exchange 134 reactions, crucial for controlling the reduced intracellular redox environment, cell 135 proliferation and growth, defence against oxidative stress or control of apoptosis. 136 Moreover, this system participates in the synthesis of deoxyribonucleotides for DNA 137 synthesis and is involved in cancer protection [40]. The two main thioredoxin 138 reductases are thioredoxin reductase 1 (TXNRD1), a cytosolic and nuclear form, and 139 thioredoxin reductase 2 (TXNRD2), which is found only as a mitochondrial form [41]. 140 TXNRDs are highly expressed in thyroid cells [8]. 141 Specifically, type 1 and 2 deiodinases (DIO1 and DIO2) activate THs, while type 3 142 deiodinases (DIO3) inactivate both tetraiodothyronine (T4) and 3,5,3′-triiodothyronine 143 (T3) [42]. DIO1 is mainly found in the liver, kidneys and thyroid [43]. In humans, most 144 of the circulating T3 is derived from the conversion of T4 to T3 by the actions of DIO1 145 [44]. Unlike DIO1, the primary function of DIO2 is believed to be the supply of T3 to 146 the nucleus so as to meet intracellular needs, as it is a subcellularly located 147 selenoprotein that appears in muscle, brain, heart, bone and brown adipose tissue [45]. 148 DIO2 is important in determining T3 content in developing tissues and the adult brain, 149 and in promoting the process of adaptive thermogenesis in brown adipose tissue. In 150 particular, DIO2 plays a primary role in T4-mediated negative feedback in the pituitary 151 gland and hypothalamus, in which T4 inhibits the expression of thyroid stimulating 152 hormone (TSH) and thyrotropin-releasing hormone (TRH), respectively [33]. DIO3 is 153 the physiological inactivator of THs, which acts by catalysing the deiodination of T4 154 into reverse triiodothyronine (rT3) and converts T3 into 3,3`diiodothyronine (T2) [46]. 155 This enzyme controls the local homeostasis of THs and protects tissues from their 156 excess [47]. Deiodinases appear to occupy a special place in the hierarchy in cases of 157 selenium deficiencies thanks to the existence of a selenium accumulation and/or 158 redistribution system in the thyroid gland [39]. Initial cell culture and animal 159 experimental studies indicated that adequate nutritional selenium supply appears to limit 160 expression of functional deiodinases during development and in the adult organism. 161 However, the deiodinative turnover of thyroid hormones requires only minimal amounts 162 of active enzymes, in contrast to enzymatic pathways acting on abundant metabolic 163 intermediates (e.g. carbohydrate, fatty acid, aminoacido or proteins). This might be one 164 of the reasons why inadequate intake of the essential trace element selenium does not 165 initially manifest as impaired deiodinase activity, but rather affects those metabolic 166 pathways, which are catalyzed by more abundant selenoenzymes acting at higher 167 substrate concentrations. These include GPxs and TXNRD involved in celular redox 168 control, several endoplasmatic reticulum-associated selenoproteins as well as 169 selenoprotein N (SELENON), all of which contribute to protein biosynthesis or 170 represente structural componentes of cells and tissues [6]. Although small amounts of 171 Se are required for the activity of DIOs, a deficiency of this nutrient decreases THs 172 synthesis and has a major impact on thyroid function [48]. Decreased production of THs 173 5 leads to stimulation of the TRH-TSH-THs axis, due to lack of control of negative 174 feedback, increasing the production of TSH [36]. 175 Finally, other selenoproteins, including selenoprotein P, K, S (SELENOP, SELENOK, 176 and SELENOS, respectively) as well as SELENON are actively secreted in the 177 thyrocytes. SELENOP is actively secreted together with GPx3 to protect thyrocytes 178 from H2O2 at the colloid in absence of TSH, while the rest of the selenoproteins, within 179 the endoplasmatic reticulum, take part in the quality control pathways [28, 49, 50]. The 180 biosynthesis of these protective selenoproteins is mainly affected by genotype, Se 181 availability, and inflammatory cytokines [28, 49]. 182 3. Selenium and thyroid cancer 183 Se is recognised as a nutrient with many health benefits in humans and other mammals 184 such as decreasing the incidence of cancer [51]. Although the specific mechanisms are 185 not fully understood, the chemopreventive effects of Se result from its protective role on 186 cell membranes against OS, its stabilising effect on DNA and its enhancement of 187 cellular immune response [52]. This element also inhibits the proliferation of tumor 188 cells by acting on the expression of the Bcl-2 apoptosis-suppressor gene and p53 tumor 189 suppressor gene, which plays an important role in the processes of control and 190 regulation of cell lifecycle and DNA replication. Furthermore, in vitro and in vivo 191 studies have revealed that both Se compounds and selenoproteins act as anti-metastatic 192 agents, inhibiting cell motility, migration and invasion, and reducing angiogenic factors 193 [53]. Nevertheless, it is important to mention that some selenoproteins, like TXNRD1, 194 SELENOF and GPx2 exhibit a split role in preventing and promoting cancer [51]. In 195 addition, Se may exhibits a U-shape relation with cancer risk [54, 55]. 196 Various studies have been carried out to examine the relationship between Se and the 197 development of thyroid cancer (Table 1). Overall, the findings suggest a potential 198 association between lower Se concentrations and the development of thyroid cancer. 199 Kucharzewski et al. [56] found that whole blood Se concentrations in a group of 200 patients (n=21) with thyroid cancer were significantly lower (0.57 µg/g) than in a 201 control group (0.71 µg/g, p < 0.01). There is no information as to the histological types 202 of cancer included in the research. Moncayo et al. [57], in a study of patients with 203 benign and malignant thyroid pathologies taking thyroid medication found that serum 204 Se levels were lower in patients with papillary (n=73) (0.080 ± 0.020 µg/ml) and 205 follicular (n=42) (0.077 ± 0.021 µg/ml) carcinoma than in the control group (0.091 ± 206 0.021 µg/ml), p = 0.015 and p = 0.031 respectively). On the other hand, Przybylik207 Mazurek et al. [58] found no significant changes in Se levels in the serum of patients 208 with papillary carcinoma (n=25) and in that of patients with follicular carcinoma (n=13) 209 compared with a control group. The same finding was noted for glutathione peroxidase 210 3 (GPx3) activity. The tumours were diagnosed histologically on routine basis, after 211 surgery. The lag time between surgery and this study examination ranged between 8 and 212 120 months, with mean ± SD of 42.9 ± 25.3 months. Patients with carcinomas were 213 receiving thyroid medication. Subsequently, in 2013, Jonklaas et al. [59] conducted a 214 study involving a group of euthyroid patients with indication for thyroidectomy for 215 suspected thyroid cancer or nodular disease. Of the cohort, 48 patients had differentiated 216 thyroid carcinoma and 17 had benign thyroid pathology. 33 of patients with 217 6 differentiated thyroid carcinoma had papillary carcinoma. Blood samples were obtained 218 two to four weeks before thyroidectomy. In the final analysis, although Se 219 concentrations were not significantly lower in thyroid cancer patients, they were 220 inversely correlated with disease stage (p = 0.011). 221 222 223 Authors, year Study design Description of participants Blood Se levels Main results Reference 7 224 Table 1. Summary of the most important clinical trials examining the relation between 225 blood Se levels and thyroid cancer. TXRFtotal-reflection X-ray fluorescence, AAS226 atomic absorption spectrometry, ICP-AESinductively coupled plasma - atomic 227 emission spectrometry. 228 229 In 2017, Baltaci et al. [60] conducted a study to examine the changes in serum Se levels 230 before, immediately after and fifteen days after thyroidectomy in patients (n=30) with 231 Kucharzewski et al., 2003 - Cross - sectional study - Thyroid cancer (n=21) - Control (n= 50) - Whole blood (TXRF) - 0.57 ± 0.12 (µg/g) - 0.71 ± 0.06 (µg/g) - Whole blood Se levels were significantly lower in the group of patients with thyroid cancer vs. control group (p < 0.01) [56] Moncayo et al., 2008 - Cross - sectional study - Papillary carcinoma (n=73) - Follicular carcinoma (n= 42) - Control (n= 554) - Serum (AAS) - 0.080 ± 0.020 (µg/ml) - 0.077 ± 0.021 (µg/ml) - 0.091 ± 0.021 (µg/ml) - Serum Se levels were significantly lower in patients with papillary and and folicular carcinoma vs. control group ( p = 0.015 and p = 0.031 respectively) [57] PrzybylikMazurek et al., 2011 - Cross - sectional study - Papillary carcinoma (n=25) - Follicular carcinoma (n= 13) - Control (n=20) - Serum (AAS) - 0.78 ± 0.12 (μM/L) - 0.80 ± 0.14 (μM/L) - 0.76 ± 0.12 (μM/L) - No significant differences among the groups in serum Se levels [58] Jonklaas et al., 2013 - Cross - sectional study - Differentiated thyroid carcinoma (n=48) - Benign thyroid disease (n= 17) - Serum (AAS) - 0.116 ± 0.014 (µg/ml) - 0.117 ± 0.010 (µg/ml) - No significant differences among the groups in serum Se levels - Serum Se levels were inversely correlated with thyroid cancer stage (p=0.011) [59] Baltaci et al., 2017 - Cross - sectional study - Group 1: male thyroid cancer patients group (n = 15) - Group 2: female thyroid cancer patients group - (n = 15); - Group 3: male control group (n = 10) - Group 4: female control group (n = 10). - Serum (ICP-AES) Pre-operative (μg/dl) - Group 1: 52.4 ± 5.6 - Group 2: 50.5 ± 4.8 - Group 3: 70.1 ± 6.9 - Group 4: 66.9 ± 7.3 Postoperative (μg/dl) - Group 1: 54.6 ± 5.5 - Group 2: 51.7 ± 5.2 - Group 3: 69.5 ± 7.1 - Group 4: 67.6 ± 5.9 15 days after the operation (μg/dl) - Group 1: 70.6 ± 5.9 - Group 2: 70.2 ± 5.5 - Group 3: 72.5 ± 6.5 - Group 4: 68.6 ± 8.0 - Preand postoperative serum Se concentrations in patients with thyroid cancer were significantly lower in serum vs. control groups (p < 0.05) - 15 days after the operation, insignificant differences were detected in serum Se concentrations among the groups [60] Mehl et al., 2020 - Cross - sectional study - Thyroid patients (n=323) - Control (n=200) - Serum (TXRF) - 76.9 ±18.8 (µg/L) - 85.1 ± 17.4 (µg/L) - A high fraction of patients (37.5%) was classified as Sedeficient (serum Se concentrations <70 μg/L), in particular the patients with thyroid malignancy (59%) [61] 8 thyroid cancer (papillary carcinoma). In addition, thyroid tissue samples were taken 232 from all subjects in the postoperative period. Serum Se levels were significantly 233 decreased (p < 0.05) before and immediately after surgery compared with the controls. 234 Fifteen days later Se levels were similar to those found in the control group. Thyroid Se 235 levels postoperatively were significantly higher (p < 0.05) than those of the controls. 236 The fact that the same patients have less Se in their serum indicates, according to the 237 authors, that Se is retained excessively in the thyroid and that changes in the levels of 238 this mineral could be related to the pathogenesis of thyroid cancer. Very recently, Mehl 239 et al. [61] carried out a study to assess the levels of trace elements (iodine, Se, copper 240 and zinc) in patients with thyroid pathologies in a European metropolis. The authors 241 found that patient serum Se values were lower than those in control group participants 242 (p < 0.0001) More importantly, it was found that it was in the group of patients with 243 thyroid malignancy (n= 17) that a higher fraction of Se deficient patients were found 244 (59%). 245 It is not yet clear whether the decrease in serum Se levels detected in most studies on 246 thyroid cancer is a consequence or a cause of the disease or if it is simply associated 247 with related pro-inflammatory conditions that alter the expression and secretion of 248 hepatic selenoprotein P, the main contributor to the Se content in serum [6]. A decrease 249 in this protein may be a phenomenon secondary to negative regulation triggered by 250 inflammatory mediators such as tumour necrosis factor α (TNF-α), interleukin 1 β (IL-1 251 β) and interferon γ (IFNγ) [62, 63]. 252 4. Selenoproteins and thyroid cancer 253 Se is co-translationally inserted in protein as the 21st amino acid, Sec and accounts for a 254 vast majority of the biological activities of Se [64]. Twenty-five selenoproteins have 255 been identified in the human proteome and twenty-four in rat and mouse proteome [65]. 256 The share of selenium in the metabolic pathways associated with the protection of cells 257 against oxidative stress causes changes in the activity of selenoproteins. Selenoprotein 258 expression is regulated by the concentration of this element [66, 67]. However, there are 259 differences in protein expression. These differences are the result of changes in mRNA 260 translation or the reduction of its stability (increased degradation) [67]. 261 There have also been several studies relating the activity and expression of seleno262 proteins with thyroid cancer, the most studied being the DIO1 and DIO2 implicated in 263 the control of THs turnover, and GPx1, GPx3 and TXNRD1, which protect thyroid 264 from OS-damage [11, 21, 68, 69, 70, 71, 72, 73, 74]. 265 4.a. Selenoproteins implicated in the control of THs turnover 266 Deiodinase expression patterns in thyroid cancers vary and depend on the type and 267 differentiation of the tumour stage. T3 is known to regulate the expression and/or 268 activity of tumour suppressors genes and oncogenes. Thus, local alterations in the 269 expression and activity of DIOs may have the potential to influence carcinogenesis [75]. 270 Different studies in papillary and follicular carcinomas support this fact. In 2005, 271 Arnaldi et al. [68] found that DIO1 and DIO2 were underexpressed in papillary 272 carcinoma following evaluation using cDNA analysis of three thyroid cancer cell lines. 273 In the same year, Ambroziak et al. [69] identified significantly decreased levels of DIO1 274 9 and DIO2 expression (p = 0.017 and p = 0.012, respectively) in papillary carcinoma 275 samples compared to control group samples (thyroid tissue from a non-cancer affected 276 part in human patients) and Meyer et al. [70] found in human patients that DIO1 277 expression and activity were decreased in papillary carcinoma samples compared to 278 surrounding normal tissue (0.25 ± 0.24 vs. 1.09 ± 0.54 arbitrary units (AU), p < 0.001 279 and 0.08 ± 0.07 vs. 0.24 ± 0.15 pmol T4/min/mg protein, p = 0.045, respectively). 280 However, in the latter study, the authors found a significant increase in DIO1 expression 281 and activity in tissue samples with follicular carcinoma (1.2 ± 0.46 vs. 0.67 ± 0.18 AU, 282 p = 0.038 and 1.20 ± 0.58 vs. 0.20 ± 0.10 pmol T4/min/mg protein, p < 0·001, 283 respectively). They also detected an increase in DIO2 activity in tissue samples with 284 metastatic follicular carcinoma (5.20 ± 0.81 vs. 0.30 ± 0.27 fmol T4/min/mg protein, p 285 < 0.001) Subsequently, Romitti et al. [76] analysed the expression and activity of DIO3 286 in papillary carcinoma human samples. The researchers observed that the augmentations 287 in D3 activity were paralleled by increased DIO3 mRNA levels (approximately 288 fivefold). They also found a positive correlation between tumour size and DIO3 activity 289 (r=0.68, p=0.003). Finally, they found that an increase in DIO3 activity in tumour 290 samples was associated with more advanced disease at diagnosis. 291 Taken together, one could posit that the changes found in the expressions of DIOs in 292 papillary carcinoma samples could cause a decrease in intracellular hormones and 293 favour tumour proliferation. Increased DIO3 and decreased DIO1 and DIO2, leading to 294 decreased T3 concentrations, could provide an advantage for tumour cell proliferation, 295 as THs can block oncogenic Ras-mediated proliferation, which specifically interferes 296 with the activity of the mitogen-activated protein kinase (MAPK) signalling pathway 297 [71]. This pathway has previously been implicated in DIO3 overregulation in other 298 pathological changes [77,78]. Genetic alterations leading to the activation of this 299 pathway are a distinguishing marker of papillary thyroid carcinoma [76]. It is known 300 that DIO3 is upregulated in the papillary thyroid carcinoma-derived cell line, K1, by 301 transforming growth factor β 1 (TGF β 1). Furthermore, it is known that treatment with 302 the inhibitors U0126 (ERK pathway) and SB203580 (p38 pathway) leads to blocking of 303 the MAPK pathway and subsequent decrease of DIO3 and inhibition of transcriptional 304 induction of DIO3 through TGF β 1, which clearly suggests that DIO3 is positively 305 regulated through the MAPK signalling pathway [76,79]. In the development of this 306 carcinoma, the BRAF gene is one of those principally affected, with the BRAFV 600 E 307 mutation occurring frequently, through substitution of a valine for a glutamic acid at 308 position 600 [80]. In the study described above, Romitti et al. [76] found that the 309 samples in which this mutation was present were those in which there was greater DIO3 310 activity. Subsequently, Romitti et al. [81] found that activation of the sonic hedgehog 311 (SHH) pathway could also be involved in DIO3 upregulation through a signalling 312 cooperation with the MAPK pathway. SHH signalling is critical for embryogenesis and 313 other cellular processes such as proliferation and differentiation. Disruption of SHH 314 signalling leads to several human diseases and appears to contribute to the development 315 of neoplastic processes. Reactivation of SHH occurs in about 25% of human tumours 316 and has been associated with the induction of DIO3 [81-83]. 317 Interestingly, retinoic acid (RA) has been shown to induce DIO1 activity in human 318 thyroid carcinoma cell lines. RA transcriptionally increased the abundance of the p27 319 subunit of DIO1. 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