Investigation of the Oxidative Stress and DIO1 Expression in CRF Patients Accompanied With and Without Euthyroid Sick Syndrome.
Kidney & blood pressure research
BACKGROUND/AIMS:Chronic renal failure (CRF) is often accompanied by increased oxidative stress and euthyroid sick syndrome (ESS). The cause of ESS is unknown, and it is unknown whether there exists a link between oxidant stress and ESS in CRF patients. Therefore, we aim to investigate oxidative stress and type 1 deiodinase (DIO1) expression, which plays the key role in the ESS in CRF patients. METHODS:In-patients with CRF were divided into the two group: Group 1 is ESS patients consisting of 60 patients with low free triiodothyronine (FT3) and Group 2 consisting of 60 patients with normal FT3. Group 3 consisted of 60 healthy volunteers recruited as controls. The baseline clinical parameters of patients were evaluated with standard routine methods in a clinical laboratory. Serum levels of 8-isoprostane and DIO1 were measured by enzyme-linked immunosorbent assay (ELISA). Multiple regression analysis was used to analyze the relationship between oxidative stress, DIO1 and FT3. RESULTS:The concentrations of serum 8-Isoprostane in Group 1 and Group 2 were substantially higher than that of Group 3 (p< 0.05), however there was no significant difference between Group 1 and Group 2 (p=0.516). The serum DIO1 level was higher in Group 2 than in Group 1 and Group 3 (p< 0.001). Multivariate linear regression analysis revealed that the DIO1 concentration and FT3 level were not associated with the concentration of serum 8-Isoprostane. CONCLUSIONS:CRF patients showed elevated oxidative stress. The CRF patients without ESS showed higher expression of DIO1 than patients with ESS and the control group. The concentration of serum 8-Isoprostane was not correlated with FT3 and DIO1 levels.
10.1159/000490471
Current concepts and challenges to unravel the role of iodothyronine deiodinases in human neoplasias.
Goemann Iuri Martin,Marczyk Vicente Rodrigues,Romitti Mirian,Wajner Simone Magagnin,Maia Ana Luiza
Endocrine-related cancer
Thyroid hormones (THs) are essential for the regulation of several metabolic processes and the energy consumption of the organism. Their action is exerted primarily through interaction with nuclear receptors controlling the transcription of thyroid hormone-responsive genes. Proper regulation of TH levels in different tissues is extremely important for the equilibrium between normal cellular proliferation and differentiation. The iodothyronine deiodinases types 1, 2 and 3 are key enzymes that perform activation and inactivation of THs, thus controlling TH homeostasis in a cell-specific manner. As THs seem to exert their effects in all hallmarks of the neoplastic process, dysregulation of deiodinases in the tumoral context can be critical to the neoplastic development. Here, we aim at reviewing the deiodinases expression in different neoplasias and exploit the mechanisms by which they play an essential role in human carcinogenesis. TH modulation by deiodinases and other classical pathways may represent important targets with the potential to oppose the neoplastic process.
10.1530/ERC-18-0097
Iodothyronine deiodinases and cancer.
Piekiełko-Witkowska A,Nauman A
Journal of endocrinological investigation
Thyroid hormones (TH) regulate key cellular processes, including proliferation, differentiation, and apoptosis in virtually all human cells. Disturbances in TH pathway and the resulting deregulation of these processes have been linked with neoplasia. The concentrations of TH in peripheral tissues are regulated via the activity of iodothyronine deiodinases. There are 3 types of these enzymes: type 1 and type 2 deiodinases are involved in TH activation while type 3 deiodinase inactivates TH. Expression and activity of iodothyronine deiodinases are disturbed in different types of neoplasia. According to the limited number of studies in cancer cell lines and mouse models changes in intratumoral and extratumoral T3 concentrations may influence proliferation rate and metastatic progression. Recent findings showing that increased expression of type 3 deiodinases may lead to enhanced tumoral proliferation support the idea that deiodinating enzymes have the potential to influence cancer progression. This review summarizes the observations of impaired expression and activity in different cancer types, published to date, and the mechanisms behind these alterations, including impaired regulation via TH receptors, transforming growth factor-β, and Sonic-hedgehog pathway. Possible roles of deiodinases as cancer markers and potential modulators of tumor progression are also discussed.
10.3275/7754
Deiodinases and Cancer.
Nappi Annarita,De Stefano Maria Angela,Dentice Monica,Salvatore Domenico
Endocrinology
Hormones are key drivers of cancer development, and alteration of the intratumoral concentration of thyroid hormone (TH) is a common feature of many human neoplasias. Besides the systemic control of TH levels, the expression and activity of deiodinases constitute a major mechanism for the cell-autonomous, prereceptoral control of TH action. The action of deiodinases ensures tight control of TH availability at intracellular level in a time- and tissue-specific manner, and alterations in deiodinase expression are frequent in tumors. Research over the past decades has shown that in cancer cells, a complex and dynamic expression of deiodinases is orchestrated by a network of growth factors, oncogenic proteins, and miRNA. It has become increasingly evident that this fine regulation exposes cancer cells to a dynamic concentration of TH that is functional to stimulate or inhibit various cellular functions. This review summarizes recent advances in the identification of the complex interplay between deiodinases and cancer and how this family of enzymes is relevant in cancer progression. We also discuss whether deiodinase expression could represent a diagnostic tool with which to define tumor staging in cancer treatment or even a therapeutic tool against cancer.
10.1210/endocr/bqab016
Disturbed expression of type 1 iodothyronine deiodinase splice variants in human renal cancer.
Piekielko-Witkowska Agnieszka,Master Adam,Wojcicka Anna,Boguslawska Joanna,Brozda Izabela,Tanski Zbigniew,Nauman Alicja
Thyroid : official journal of the American Thyroid Association
BACKGROUND:Alternative splicing, one of the sources of protein diversity, is often disturbed in cancer. Type 1 iodothyronine deiodinase (DIO1) catalyzes deiodination of thyroxine generating triiodothyronine, an important regulator of cell proliferation and differentiation. The expression of DIO1 is disturbed in different types of cancer. The aim of the study was to analyze the alternative splicing of DIO1 and its possible disturbance in renal cancer. METHODS:Using real-time PCR, we analyzed 19 tissue samples (T) of renal cancer and 19 matched control samples (C) of the opposite pole of the kidney, not infiltrated by tumor, and 6 control samples (N) (nonneoplastic kidney abnormalities). RESULTS:Cloning of DIO1 mRNA isoforms revealed 11 different transcripts, among them 7 new splice variants, not previously reported. The expression of all variants of DIO1 was dramatically (>90%) and significantly (p < or = 0.0003) lowered in samples T compared to control samples C. The ratio of mRNA isoforms encoding DIO1 protein variants possessing or lacking the active center was lowered in samples T compared with control samples C, suggesting disturbed alternative splicing of DIO1. The expression of mRNA of splicing factors SF2/ASF (splicing factor-2/alternative-splicing factor) and hnRNPA1 (heterogeneous ribonucleoprotein A1), regulating 5'-splice site selection, was significantly but not proportionally lowered in samples T compared to samples C. The mRNA ratio of splicing factors SF2/ASF and hnRNPA1 correlated with the ratio of mRNA isoforms encoding DIO1 protein variants possessing or lacking the active center in controls C but not in samples T. CONCLUSIONS:Our results show that the expression and alternative splicing of DIO1 mRNA is disturbed in renal cancer, possibly due to changes in expression of splicing factors SF2/ASF and hnRNPA1.
10.1089/thy.2008.0284
MiR-224 targets the 3'UTR of type 1 5'-iodothyronine deiodinase possibly contributing to tissue hypothyroidism in renal cancer.
Boguslawska Joanna,Wojcicka Anna,Piekielko-Witkowska Agnieszka,Master Adam,Nauman Alicja
PloS one
Type 1 iodothyronine deiodinase (DIO1) catalyses the conversion of prohormone thyroxine to the active thyroid hormone 3,3',5-triiodothyronine (T3), important regulator of cell proliferation and differentiation. DIO1 expression is reduced in the most common type of kidney neoplasia, clear cell Renal Cell Carcinoma (ccRCC). MicroRNAs are small, non-coding RNAs that regulate gene expression at posttranscriptional levels. The aim of this study was to analyze the potential regulation of DIO1 expression by microRNAs in ccRCC. Bioinformatic analysis revealed that 3'UTR of the human DIO1 gene transcript contains miR-224 and miR-383 target sites, which are conserved across mammalian species. Semi-quantitative real-time PCR was used to analyze the expression of miR-224 and miR-383 in 32 samples of ccRCC tumors (T) and in 32 matched control (C) samples. We observed statistically significant (p = 0.0002) more than four fold increase in miR-224 expression and nearly two fold increase in miR-383 expression in samples T compared to samples C. Tumor specific changes in expression of miR-224 negatively correlated with changes in DIO1 expression and intracellular T3 concentration. Transfection of HeLa cell line with miR-224 and miR-383 suppressed the activity of a luciferase reporter containing the 3'UTR of DIO1. This was abolished when constructs mutated at the miR-224 and miR-383 target sites were used instead, indicating that miR-224 and miR-383 directly bind to DIO1 3'UTR. Finally, induced expression of miR-224 in Caki-2 cells resulted in significant (p<0.01) reduction of DIO1 mRNA. This study provides a novel miRNA-mediated regulatory mechanism of DIO1 expression in ccRCC.
10.1371/journal.pone.0024541
Induction of type 1 iodothyronine deiodinase expression inhibits proliferation and migration of renal cancer cells.
Poplawski Piotr,Rybicka Beata,Boguslawska Joanna,Rodzik Katarzyna,Visser Theo J,Nauman Alicja,Piekielko-Witkowska Agnieszka
Molecular and cellular endocrinology
Type 1 iodothyronine deiodinase (DIO1) regulates peripheral metabolism of thyroid hormones that control cellular proliferation, differentiation and metabolism. The significance of DIO1 in cancer is unknown. In this study we hypothesized that diminished expression of DIO1, observed in renal cancer, contributes to the carcinogenic process in the kidney. Here, we demonstrate that ectopic expression of DIO1 in renal cancer cells changes the expression of genes controlling cell cycle, including cyclin E1 and E2F5, and results in inhibition of proliferation. The expression of genes encoding collagens (COL1A1, COL4A2, COL5A1), integrins (ITGA4, ITGA5, ITGB3) and transforming growth factor-β-induced (TGFBI) is significantly altered in renal cancer cells with induced expression of DIO1. Finally, we show that overexpression of DIO1 inhibits migration of renal cancer cells. In conclusion, we demonstrate for the first time that loss of DIO1 contributes to renal carcinogenesis and that its induced expression protects cells against cancerous proliferation and migration.
10.1016/j.mce.2016.12.004