Redox Homeostasis in Thyroid Cancer: Implications in Na+/I- Symporter (NIS) Regulation.

Radioiodine therapy (RAI) is a standard and effective therapeutic approach for differentiated thyroid cancers (DTCs) based on the unique capacity for iodide uptake and accumulation of the thyroid gland through the Na+/I- symporter (NIS). However, around 5-15% of DTC patients may become refractory to radioiodine, which is associated with a worse prognosis. The loss of RAI avidity due to thyroid cancers is attributed to cell dedifferentiation, resulting in NIS repression by transcriptional and post-transcriptional mechanisms. Targeting the signaling pathways potentially involved in this process to induce de novo iodide uptake in refractory tumors is the rationale of "redifferentiation strategies". Oxidative stress (OS) results from the imbalance between ROS production and depuration that favors a pro-oxidative environment, resulting from increased ROS production, decreased antioxidant defenses, or both. NIS expression and function are regulated by the cellular redox state in cancer and non-cancer contexts. In addition, OS has been implicated in thyroid tumorigenesis and thyroid cancer cell dedifferentiation. Here, we review the main aspects of redox homeostasis in thyrocytes and discuss potential ROS-dependent mechanisms involved in NIS repression in thyroid cancer.

TGF-ß1 Disrupts redox balance in PCCL3 thyroid cell and is sexually dimorphic expressed in rat thyroid gland.

Thyroid diseases are more prevalent in women, and this difference seems to be associated with the oxidative stress found in the thyroid of females. Thyroid NADPH Oxidase 4 (NOX4) was shown to respond to estrogen, which can also modulate TGF-ß1, a potent stimulator of NOX4. This study aimed to investigate the effects of TGF-ß1 on redox homeostasis parameters in the rat thyroid cell PCCL3 and the interrelationship between estrogen and TGF-ß1. TGF-ß1 treatment increased both intra- and extracellular ROS generation along with NOX4 expression and reduced GPX and catalase activities, extracellular H2O2 scavenging capacity, and reduced thiol content. TGF-ß1 mRNA and protein expression are higher in female thyroid glands of rats in comparison to males. Moreover, 17ß-estradiol treatment enhanced TGF-ß1 mRNA in PCCL3 cells, decreased extracellular bioavailability but did not activate Smad pathway. Our data suggest that higher levels of TGF-ß1 in females are potentially related to higher ROS availability which may be associated with the sex disparity in thyroid disorders.

Differential Expression of HMGA1 and HMGA2 in pituitary neuroendocrine tumors.

Defining biomarkers for invasive pituitary neuroendocrine tumors (PitNETs) is highly desirable. The high mobility group A (HMGA) proteins are among the most widely expressed cancer-associated proteins. Indeed, their overexpression is a frequent feature of human malignancies, including PitNETs. We show that nonfunctioning PitNETs (NF-PitNETs) express significantly higher levels of HMGA1 than somatotropinomas (GHs) and corticotropinomas (ACTHs). Furthermore, HMGA2 expression was detected only in NF-PitNETs and was significantly higher in larger tumors than in smaller tumors. HMGA expression analysis generally focuses on nuclear staining. Here, cytoplasmic HMGA staining was also found. PitNETs displayed strong nuclear HMGA1 and strong cytoplasmic HMGA2 immunoreactivity. Interestingly, the HMGA1 and HMGA2 nuclear expression levels were significantly higher in invasive adenomas than in noninvasive adenomas. The highest levels of nuclear HMGA2 were found in GHs. In conclusion, we show that overexpression of nuclear HMGA proteins could be a potential biomarker of invasive PitNETs, particularly HMGA2 for GHs. HMGA2 might be a reliable biomarker for NF-PitNETs.

[Profile of body composition in women with class III obesity by multipolar bioimpedance method]. / Perfil da composição corporal de mulheres com obesidade grau III pelo método de bioimpedância multipolar.

OBJECTIVE: To analyze a body composition profile in women with class III obesity using the multipolar bioimpedance method. METHODS: Thirteen sedentary women aged between 20 and 40 years were evaluated. RESULTS: The results show that the patients had a fat percentage of 51.9±1.50 % and lean mass of 48.1±1.50 %. Regarding fat mass and lean mass per body region, figures of 26.3±3.62kg and 26.2±2.91kg in the upper body, 9.1±0.06kg and 8.4±0.14kg in the lower limbs, and 3.3±0.02kg and 7.6±0.01kg in the upper limbs were obtained. Patients had a good symmetry between the left and right sides in both upper and lower limbs, besides of a muscular mass of 32.1±5.08kg, with a muscular mass index of 12.7±1.05kg/m2. CONCLUSION: Higher fat accumulation was observed in the upper body region, followed by lower and upper limbs. Total muscular mass was apparently preserved, although sarcopenic obesity was not verified. Since this is a group of people that is still understudied, there is a need for further research on genetic and physical profile and caloric expenditure during exercise and rest.

Flavonoid rutin increases thyroid iodide uptake in rats.

Thyroid iodide uptake through the sodium-iodide symporter (NIS) is not only an essential step for thyroid hormones biosynthesis, but also fundamental for the diagnosis and treatment of different thyroid diseases. However, part of patients with thyroid cancer is refractory to radioiodine therapy, due to reduced ability to uptake iodide, which greatly reduces the chances of survival. Therefore, compounds able to increase thyroid iodide uptake are of great interest. It has been shown that some flavonoids are able to increase iodide uptake and NIS expression in vitro, however, data in vivo are lacking. Flavonoids are polyhydroxyphenolic compounds, found in vegetables present in human diet, and have been shown not only to modulate NIS, but also thyroperoxidase (TPO), the key enzyme in thyroid hormones biosynthesis, besides having antiproliferative effect in thyroid cancer cell lines. Therefore, we aimed to evaluate the effect of some flavonoids on thyroid iodide uptake in Wistar rats in vivo. Among the flavonoids tested, rutin was the only one able to increase thyroid iodide uptake, so we decided to evaluate the effect of this flavonoid on some aspects of thyroid hormones synthesis and metabolism. Rutin led to a slight reduction of serum T4 and T3 without changes in serum thyrotropin (TSH), and significantly increased hypothalamic, pituitary and brown adipose tissue type 2 deiodinase and decreased liver type 1 deiodinase activities. Moreover, rutin treatment increased thyroid iodide uptake probably due to the increment of NIS expression, which might be secondary to increased response to TSH, since TSH receptor expression was increased. Thus, rutin might be useful as an adjuvant in radioiodine therapy, since this flavonoid increased thyroid iodide uptake without greatly affecting thyroid function.