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PubMed1981

Early kinetics of thyroid trap in normal human patients and in thyroid diseases.

A six-compartment model is proposed for the study of early iodine kinetics (150 min) in the human thyroid gland including three compartments for extrathyroidal spaces. The results were compared with those obtained with an open two-compartment thyroid model. In six euthyroid subjects the values of the unidirectional thyroid clearance R41 = 86 +- 25 ml/min and of the irreversible clearance R65 = 22 +- 9 ml/min were consistent with those generally accepted. With TSH stimulation a clear increase in the thyroidal pump effectiveness was found without an increase in the irreversible clearance. In four untreated thyrotoxic patients a tenfold increase in the unidirectional thyroid clearance was found (p less than 0.01). The binding rate was much less increased and overlapped with the normal values; a large increase in the iodide compartment volumes was found. The unidirectional clearance remained elevated in seven patients after Carbimazole treatment and the binding rates were reduced. The six-compartment model demonstrated a rapid exit from the bound iodine compartment. In three of four goitrous patients studied, the thyroid unidirectional clearance was significantly increased ( p less than 0.001). The volumes of the iodide compartments were much higher than those observed in the other groups. The method was applied to analyse the kinetics of the different parts of the thyroid.

Antithyroid Agents↗
PubMed2001

Medullary thyroid cancer, papillary thyroid microcarcinoma and Graves' disease: an unusual clinical coexistence.

We describe the unusual case of a Caucasian woman who had a diagnosis of medullary thyroid cancer and papillary microcarcinoma 5 years after a diagnosis of Graves' disease. The patient came to our observation for recurrence of hyperthyroidism. An ultrasound scan revealed diffuse thyroid enlargement with a nodule, recently increased in size. The serum CT and carcinoembrional antigen were elevated, and the fine-needle aspiration cytology with immunocytochemical analysis for CT was suggestive for medullary thyroid carcinoma. The nodular lesion showed intense 111In-pentetreotide uptake, whereas total body scintigraphy with the same tracer and with Thallium-201, 99mTc (V) dimercaptosuccinic acid was negative for lymph node and distant metastasis. The histological examination of thyroidectomy specimens confirmed the diagnosis of medullary thyroid cancer, showing a lymphocytic intratumoral infiltration. The histological analysis of the controlateral lobe showed an occult papillary microcarcinoma. Medullary thyroid carcinoma and papillary microcarcinoma showed intense staining with policlonal anti-RET antibodies, although genetic analysis was negative for RET mutations most frequently involved in familial and sporadic medullary thyroid carcinomas. Possible implications about the coexistence of the 3 thyroid diseases are discussed.

Adult↗
PubMed1983

The adaptation of the human thyroid gland to a physiological regimen of iodide intake: evidence for a transitory inhibition of thyroid hormone secretion modulated by the intrathyroidal iodine stores.

The effects of iodide on thyroid function were so far only studied after administration of pharmacological or small continuous doses. We were interested to know how the human thyroid gland would react to a more physiological situation: small doses taken in intermittently. Ten normal male volunteers were given weekly doses of iodide: 1 mg for the first 6 weeks and 2 mg afterwards for another 6 weeks period. Intrathyroidal iodine stores were evaluated by the X-Ray-Fluorescence method. The following thyroid parameters were estimated during the 3 months period: total thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine, reverse triiodothyronine, plasma inorganic iodide, thyroid stimulating hormone and thyrotropin-releasing hormone tests. The following observations were made: i) a steady increase of intrathyroidal iodine (p less than 0.01); ii) no changes in free thyroxine, free triiodothyronine, thyroid stimulating hormone, thyrotropin-releasing hormone test or plasma inorganic iodide. iii) a decrease of total thyroxine (and total triiodothyronine) with a nadir at about 3 weeks and a spontaneous rise afterwards; repetition of this phenomenon by doubling the dose of iodide. It is concluded that 1 mg or 2 mg iodide a week does not inhibit incorporation into the normal human thyroid gland and suggested that these physiological doses of iodide cause a transitory inhibition of thyroxine secretion, representing a form of autoregulation of the thyroid cell, since it was modulated by the intrathyroidal iodine stores and no evidence of pituitary mediation could be evidenced in the experimental protocol.

Adult↗
PubMed2005

99mTc-sestamibi thyroid uptake in euthyroid individuals and in patients with autoimmune thyroid disease.

PURPOSE: We investigated the biokinetics of (99m)Tc-sestamibi in the thyroid of euthyroid volunteers (EVs) and in patients with autoimmune thyroid diseases and determined the best time interval between (99m)Tc-sestamibi injection and calculation of uptake. METHODS: Forty EVs, 30 patients with Graves' disease (GD), 15 patients with atrophic Hashimoto's thyroiditis (AHT) and 15 patients with hypertrophic Hashimoto's thyroiditis (HHT) underwent (99m)Tc-sestamibi thyroid scintigraphy. Dynamic images were acquired for 20 min, and static images were obtained 20 min, 60 min and 120 min post injection. Five-, 20-, 60- and 120-min uptake, time to maximal uptake (T(max)) and T(1/2) of tracer clearance were calculated. Thyroid hormones and antibodies were measured. (99m)Tc-pertechnetate uptake was investigated in GD patients. RESULTS: T(max) was approximately 5 min in all four groups. The mean T(1/2) value for EVs was similar to the GD value and lower than the HHT and AHT values. The mean (+/-SD) 5-min uptake was 0.13% (+/-0.05%) for EVs. The 5-min uptake in GD was higher than that in EVs(P<0.001) and correlated with free thyroxine (r=0.54) and with (99m)Tc-pertechnetate uptake (r=0.68). Uptake in HHT was higher than that in AHT (P=0.0003) and EVs (P=0.002). Uptake in AHT was lower than uptake in EVs (P=0.0001). CONCLUSION: Five minutes is the optimal time interval between (99m)Tc-sestamibi injection and calculation of thyroid uptake. Five-minute uptake differentiates euthyroid individuals from GD patients. There is a high correlation between (99m)Tc-sestamibi and (99m)Tc-pertechnetate uptake in GD. The reduced (99m)Tc-sestamibi uptake in AHT patients is probably due to glandular destruction and fibrosis. Inflammatory infiltrate and high mitochondrial density in thyrocytes possibly explain the increased uptake in GD and HHT.

Adolescent↗
PubMed2001

Iodide uptake in human anaplastic thyroid carcinoma cells after transfer of the human thyroid peroxidase gene.

Human thyroperoxidase (hTPO) is critical for the accumulation of iodide in thyroid tissues. Poorly differentiated and anaplastic thyroid tumours which lack thyroid-specific gene expression fail to accumulate iodide and, therefore, do not respond to iodine-131 therapy. We consequently investigated whether transfer of the hTPO gene is sufficient to restore the iodide-trapping capacity in undifferentiated thyroid and non-thyroid tumour cells. The human anaplastic thyroid carcinoma cell lines C643 and SW1736, the rat Morris hepatoma cell line MH3924A and the rat papillary thyroid carcinoma cell line L2 were used as in vitro model systems. Employing a bicistronic retroviral vector based on the myeloproliferative sarcoma virus for the transfer of the hTPO and the neomycin resistance gene, the C643 cells and SW1736 cells were transfected while the L2 cells and MH3924A cells were infected with retroviral particles. Seven recombinant C643 and seven SW1736 cell lines as well as four recombinant L2 and four MH3924A cell lines were established by neomycin selection. They were studied for hTPO expression using an antibody-based luminescence kit, followed by determination of the enzyme activity in the guaiacol assay and of the iodide uptake capacity in the presence of Na125I. Genetically modified cell lines expressed up to 1,800 times more hTPO as compared to wild type tumour cells. The level of hTPO expression varied significantly between individual neomycin-resistant cell lines, suggesting that the recombinant retroviral DNA was integrated at different sites of the cellular genome. The accumulation of iodide, however, was not significantly enhanced in individual recombinant cell lines, irrespective of low or high hTPO expression. Moreover, there was no correlation between hTPO expression and enzyme activity in individual cell lines. The transduction of the hTPO gene per se is not sufficient to restore iodide trapping in non-iodide-concentrating tumour cells. Future studies will have to concentrate on the possible expression of enzymatically active proteins or the transfer of multiple genes involved in iodide trapping.

Animals↗
PubMed2004

Metastasis to the thyroid from lung adenocarcinoma mimicking thyroid carcinoma.

We herein report a case of metastasis to the thyroid from lung adenocarcinoma mimicking thyroid carcinoma. The thyroid tumor was palpated in the left lobe of the thyroid and diagnosed as primary thyroid carcinoma by fine-needle aspiration cytology. The patient also had a large pulmonary tumor and tiny pulmonary nodules, which were respectively diagnosed as moderately differentiated adenocarcinoma of the lung and intrapulmonary metastases from the main large lung carcinoma by the pathological examination of the biopsy specimens obtained by video-assisted thoracic surgery. Hemithyroidectomy with radical neck dissection was performed. The thyroid tumor was diagnosed as metastasis to the thyroid from lung adenocarcinoma, because it showed mucin production, positive immunoreactivity for carcinoembryonic antigen and negative immunoreactivities for thyroglobulin and calcitonin. The patient received systemic chemotherapy and died of the disease 1 year and 7 months after the diagnosis was made.

Adenocarcinoma↗
PubMed1993

Studies on the use of thyroid hormone and a thyroid hormone analogue in the treatment of congestive heart failure.

In heart failure, cardiac output is insufficient to meet the needs of the body for oxygen delivery. Available data suggest that alterations in thyroid hormone metabolism may contribute to defective myocardial performance. Accordingly, thyroid hormone or a thyroid hormone analogue that improves cardiac performance might be useful in the treatment of heart failure and has been studied. Experimental and theoretical results of these studies are reviewed and indicate that thyroid hormone increases cardiac output by a combination of effects on the heart and peripheral circulation, specifically by increasing myocardial contractile performance and decreasing venous compliance. In the rat postinfarction model of heart failure, treatment with low doses of thyroxine (1.5 micrograms/100 g) for 3 days produced a positive inotropic response, including an increase in rate of change of left ventricular pressure and a decrease in left ventricular end-diastolic pressure. These changes could be attributed to conversion to triiodothyronine, the active intracellular form of thyroid hormone. When treatment with thyroxine was continued at the same or higher doses (3 to 15 micrograms/100 g) for 10 to 12 days, heart rate increased and improvement in left ventricular end-diastolic pressure was not sustained. More favorable results were obtained with 3,5-diiodothyropropionic acid, a cardiotonic thyroid hormone analogue administered at doses of 375 microgram/100 g, given in combination with captopril. Thus, triiodothyronine or a thyroid hormone analogue may be a useful adjunct to other measures in the treatment of heart failure.

Animals↗
PubMed1985

Annual variations of thyroid reactivity following thyrotropin stimulation and circulating levels of thyroid hormones in the frog Rana ridibunda.

Annual variations in plasma concentration and thyroid gland content of thyroid hormones were studied in male Rana ridibunda during 2 consecutive years together with in vitro capacity of the thyroid gland to release thyroxine (T4) following stimulation with bovine thyrotropin (b-TSH). A low thyroidal content of triiodothyronine (T3) (2-4 ng) and T4 (300-400 ng) is found during winter and increases rapidly after hibernation to maximal values of +/- 50 ng T3 and 2000-2500 ng T4 in May-July. Plasma levels of T3 vary between 10 and 15 pg/ml for all months studied except for a low of 5.4 and 5.7 pg/ml in December and March, respectively. Plasma concentrations of T4 are low in winter (100-200 pg/ml) but increase in January, reaching maximal levels in February-March (700-1000 pg/ml). In the first year levels decrease again until August (last observation month) to about 250 pg/ml, whereas in the second year this decrease is more sudden, reaching winter values of 100-200 pg/ml as early as May-June. Thereafter a second increase in plasma concentrations of T4 is observed again with maximal values of 800 pg/ml obtained in October. This biphasic circannual pattern, from two different observations, is also found in the in vitro T4 release capacity of the thyroid glands following stimulation with 100 mU of b-TSH. The maximal release capacity of the thyroid glands following stimulation with 100 mU of b-TSH. The maximal release capacity of the thyroids is present in March and July-August. Minimal release capacities are present in winter but also in April-June.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Thyroid-stimulating hormone and cyclic adenosine 3',5'-monophosphate in the regulation of thyroid gland function.

The initial step in TSH action reflects binding of the hormone to specific receptor sites on the plasma membrane. Such binding has been studied using plasma membranes, homogenates, isolated thyroid cells grown in culture, and thyroid slices. 3-H- and iodinated TSH preparations have been used; the latter have been prepared using both chloramine-T and lactoperoxidase. Some of the discrepancies reported in the literature might reflect the different thyroid and hormone preparations and the variable incubation conditions which have been used. In general, good correlation exists between binding of TSH and activation of adenylate cyclase in thyroid plasma membranes. Data is reviewed related to activation of protein kinase in intact thyroid cells by TSH. Although there is impressive evidence for cyclic AMP mediation of effects of TSH on the thyroid, some data that are inconsistent with this concept are considered, especially in relationship to 32-P incorporation into phospholipid. The role of cyclic GMP in thyroid function is discussed.

Adenylyl Cyclases↗
PubMed1988

Independent effects of liver disease and chronic alcoholism on thyroid function and size: the possibility of a toxic effect of alcohol on the thyroid gland.

In an autopsy study we found thyroid volume significantly decreased in alcoholics with liver cirrhosis as compared to matched controls: 15 mL (range, 7 to 37 mL) v 25 mL (range, 13 to 90 mL) (P less than .01). At the same time the amount of fibrosis of the thyroid glands was higher in the alcoholics as compared to the matched controls: 20% (range, 6% to 40%) v 12% (range, 6% to 23%) (P less than .01). In order to evaluate the relative importance of alcohol consumption and liver disease on thyroid function and ultrasonically determined size, three groups of patients and matched controls (sex, age, weight, and smoking habits) were investigated: group 1, 18 patients with nonalcoholic liver cirrhosis; group 2, 21 consecutive chronic alcoholics (greater than 100 g of alcohol daily for greater than 5 years) without liver cirrhosis (all had biopsy proven fatty change or normal liver); group 3, 31 nonalcoholic patients with chronic nonhepatic, nonrenal disease. In group 1 median thyroid volume and serum FT4I, FT3I, and TSH levels were unchanged compared with the controls. In group 2 median thyroid volume was 13 mL (range, 9 to 32 mL) compared with 27 mL (range, 12 to 44 mL) in the controls (P less than .005). Serum T3 and FT3I levels were reduced, while T4, FT4I, and TSH levels were unaltered. In group 3 serum T3 and FT3I levels were reduced while serum FT4I and TSH levels and thyroid volume were unaltered compared with the controls. It is suggested that alcohol may have a toxic effect on the thyroid gland independent of the degree of liver damage.

Adult↗
PubMed1979

The effect of propylthiouracil on thyroid-stimulating hormone-induced alterations in iodothyronine secretion from perfused dog thyroids.

The aim of this study was to see whether the inhibitory effect of propylthiouracil on thyroidal secretion of 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) could be reproduced in intensively stimulated thyroids, and to elucidate whether an increase in the fractional deiodination of thyroxine (T4) to T3 and rT3 during iodothyronine secretion might be responsible for the transient fall in the T4/T3 and T4/rT3 ratios in thyroid secretion seen in the early phase after stimulation of thyroid secretion. For this purpose T4, T3 and rT3 were measured in effluent from isolated dog thyroid lobes perfused in a non-recirculation system using a synthetic hormone free medium. 1 mmol/1 propylthiouracil induced a significant reduction in thyroid-stimulating hormone (TSH) stimulated T3 and rT3 release while the release of T4 was unaffected. This supports our previous conclusion that T4 is partially monodeiodinated to T3 and rT3 during thyroid secretion. Infusion of 1 mmol/l propylthiouracil for 30 min or 3 mmol/l propylthiouracil for 120 min did not abolish the transient fall in effluent T4/T3 and T4/rT3 induced by TSH stimulation. Thus, this phenomenon seems not to depend on intrathyroidal iodothyronine deiodinating processes.

Animals↗
PubMed2004

TTF-2 stimulates expression of 17 genes, including one novel thyroid-specific gene which might be involved in thyroid development.

Thyroid dysgenesis is the most frequent cause of congenital hypothyroidism, but its molecular pathophysiology is largely unknown. Our hypothesis that some genes downstream to thyroid transcription factor-2 (TTF-2) might be responsible for development of the thyroid prompted us to identify genes whose expression is stimulated by TTF-2. PCR products of cDNA clones obtained by a subtraction PCR method in TTF-2 expressing cell lines were screened with labeled cDNA by microarray analysis. We isolated 17 genes up-regulated by TTF-2, which were subsequently confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR). One of them is a novel gene designated T1560 that showed a highly thyroid-specific expression pattern. Luciferase reporter assays showed that expression of all of the 14 genes tested was stimulated by both TTF-2 and TTF-1, another thyroid-specific transcription factor. Our results have important implications for understanding normal thyroid development as well as the molecular defects underlying thyroid dysgenesis.

Amino Acid Sequence↗
PubMed2004

Endocrine active compounds affect thyrotropin and thyroid hormone levels in serum as well as endpoints of thyroid hormone action in liver, heart and kidney.

To assess interference with endocrine regulation of the thyroid axis, rats (female, ovariectomised) were treated for 12 weeks with the suspected endocrine active compounds (EAC) or endocrine disrupters (ED) 4-nonylphenol (NP), octyl-methoxycinnamate (OMC) and 4-methylbenzylidene-camphor (4-MBC) as well as 17beta-estradiol (E2) and 5alpha-androstane-3beta,17beta-diol (Adiol) on the background of a soy-free or soy-containing diet, and endpoints relevant for regulation via the thyroid axis were measured. Thyrotropin (TSH) and thyroid hormone (T4, T3) serum levels were altered, but not in a way consistent with known mechanisms of feedback regulation of the thyroid axis. In the liver, malic enzyme (ME) activity was significantly increased by E2 and Adiol, slightly by OMC and MBC and decreased by soy, whereas type I 5'-deiodinase (5'DI) was decreased by all treatments. This may be due rather to the estrogenic effect of the ED, as there is no obvious correlation with T4 or T3 serum levels. None of the substances inhibited thyroid peroxidase (TPO) in vitro, except for NP. In general, several endocrine active compounds disrupt the endocrine feedback regulation of the thyroid axis. However, there was no uniform, obvious pattern in the effects of those ED tested, but each compound elicited its own spectrum of alterations, arguing for multiple targets of interference with the complex network of thyroid hormone action and metabolism.

Animals↗
PubMed2006

Thyroid disorders. Part II: hypothyroidism and thyroiditis.

Part II of the series on thyroid disorders discusses hypothyroidism and thyroiditis that may be found in dental patients. An overview of the conditions is presented. Presenting signs and symptoms, laboratory tests used to diagnose hypothyroidism and thyroiditis, and their medical management is discussed. The dental management of patients with hypothyroidism is discussed in detail. The dentist by detecting the early signs and symptoms of hypothyroidism and thyroiditis can refer the patient for medical diagnosis and treatment and avoid potential complications of treating patients with uncontrolled disease. Patients with thyroiditis may have a short period of being hyperthyroid and it may be best to avoid routine dental treatment during that period. Patients with suppurative thyroiditis should not receive routine dental treatment during the acute stage of the disease. The end stage of Hashimoto's thyroiditis results in hypothyroidism. Central nervous system depressants, sedatives, or narcotic analgesics must be avoided in patients with severe hypothyroidism because significant respiratory depression may occur. In addition, myxedematous coma, particularly in elderly hypothyroid patients, can be precipitated by central nervous system depressants, infection, and possibly stressful dental procedures. In medically well-controlled patients the dental treatment plan is not affected and most dental procedures can be offered to these patients.

Adult↗
PubMed1999

Differential expression of thyroid hormone receptor isoforms by thyroid hormone and lithium in rat GH3 and B103 cells.

BACKGROUND: The interaction between lithium, a mood stabilizer, and the thyroid axis has been extensively studied; however, the regulation of thyroid hormone receptors by lithium is yet to be investigated. METHODS: To test whether lithium affects thyroid hormones at the receptor level, we examined the effects of lithium in combination with triiodothyronine (T3) on gene expression of thyroid hormone receptor isoforms in GH3 and B103 cells. RESULTS: The pattern of expression as well as the magnitude of regulation of the different thyroid hormone receptor isoforms appeared to be cell line specific. Whereas T3 regulated all four isoforms in GH3 cells at both time points, T3 did not alter thyroid hormone receptor TR alpha 1 and TR alpha 2 mRNA in B103 cells. Addition of lithium to thyroid hormone-deficient GH3 cells decreased TR alpha 1, alpha 2, and beta 2 expression without affecting TR beta 1 expression at 2 but not 5 days. Addition of lithium to T3-treated GH3 cells did not further modulate gene expression of TR alpha 1, alpha 2, beta 1, or beta 2 when compared to cells treated with T3 alone. The effects of lithium in B103 cells appeared to be isoform specific as well as time dependent, since TR alpha 1 expression was selectively decreased in B103 cells, when treated with T3 in the presence of lithium. CONCLUSIONS: The present study provides direct evidence that T3 and/or lithium regulate TR gene expression in vitro in a both time-dependent and cell line-specific manner.

Adenoma↗
PubMed1997

Induction of manganese superoxide dismutase by thyroid stimulating hormone in rat thyroid cells.

Alterations in the superoxide dismutase (SOD) content of thyroid tissues occurring in association with thyroid dysfunction have been reported. In this study, the Mn-SOD content was found to increase in thyroid tissues of rats administered thyroid stimulating hormone (TSH) and in thyrocytes cultured in medium supplemented with TSH. Furthermore, in the thyroid glands of rats whose serum TSH level was elevated by inhibiting the synthesis of T3 and T4 by 6-methyl-2-thiouracil, the Mn-SOD increased as the TSH concentration increased. In the cultured thyrocytes, the increase in Mn-SOD induced by TSH was inhibited by the C-kinase inhibitor H7. These findings suggest the induction of Mn-SOD by TSH in thyroid cells and point to a role of C-kinase in this process, thereby indicating that a close relationship exists between the serum TSH level and the change in Mn-SOD content in thyrocytes with thyroid dysfunction.

Animals↗
PubMed2003

Induction of T(4) UDP-GT activity, serum thyroid stimulating hormone, and thyroid follicular cell proliferation in mice treated with microsomal enzyme inducers.

The microsomal enzyme inducers phenobarbital (PB), pregnenolone-16 alpha-carbonitrile (PCN), 3-methylcholanthrene (3MC), and Aroclor 1254 (PCB) are known to induce thyroxine (T(4)) glucuronidation and reduce serum T(4) concentrations in rats. Also, microsomal enzyme inducers that increase serum TSH (i.e., PB and PCN) also increase thyroid follicular cell proliferation in rats. Little is known about the effects of these microsomal enzyme inducers on T(4) glucuronidation, serum thyroid hormone concentrations, serum TSH, and thyroid gland growth in mice. Therefore, we tested the hypothesis that microsomal enzyme inducers induce T(4) UDP-GT activity, resulting in reduced serum T(4) concentrations, as well as increased serum TSH and thyroid follicular cell proliferation in mice. B6C3F male mice were fed a control diet or a diet containing PB (600, 1200, 1800, or 2400 ppm), PCN (250, 500, 1000, or 2000 ppm), 3MC (62.5, 125, 250, or 500 ppm), or PCB (10, 30, 100, or 300 ppm) for 21 days. All four inducers increased liver weight and hepatic microsomal UDP-GT activity toward chloramphenicol, alpha-naphthol, and T(4). PB and PCB decreased serum total T(4), but PCN and 3MC did not. Serum thyroid stimulating hormone was markedly increased by PCN and 3MC treatments, and slightly increased by PB and PCB treatments. All four microsomal enzyme inducers dramatically increased thyroid follicular cell proliferation in mice. The findings suggest that PB, PCN, 3MC, and PCB disrupt thyroid hormone homeostasis in mice.

Administration, Oral↗
PubMed2000

PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated by p27kip1.

The dual-specificity phosphatase PTEN/MMAC1/TEP1 has recently been identified as the tumor suppressor gene most frequently mutated and/or deleted in human tumors. Germline mutations of PTEN give rise to Cowden Disease (CD), an autosomal dominantly-inherited cancer syndrome which predisposes to increased risk of developing breast and thyroid tumors. However, PTEN mutations have rarely been detected in sporadic thyroid carcinomas. In this study, we confirm that PTEN mutations in sporadic thyroid cancer are infrequent as we found one point mutation and one heterozygous deletion of PTEN gene in 26 tumors and eight cell lines screened. However, we report that PTEN expression is reduced both at the mRNA and at the protein level - in five out of eight tumor-derived cell lines and in 24 out of 61 primary tumors. In most cases, decreased PTEN expression is correlated with increased phosphorylation of the PTEN-regulated protein kinase Akt/PKB. Moreover, we demonstrate that PTEN may act as a suppressor of thyroid cancerogenesis as the constitutive re-expression of PTEN into two different thyroid tumor cell lines markedly inhibits cell growth. PTEN-dependent inhibition of BrdU incorporation is accompanied by enhanced expression of the cyclin-dependent kinase inhibitor p27kip1 and can be overcome by simultaneous co-transfection of an excess p27kip1 antisense plasmid. Accordingly, in a subset of thyroid primary carcinomas and tumor-derived cell lines, a striking correlation between PTEN expression and the level of p27kip1 protein was observed. In conclusion, our findings demonstrate that inactivation of PTEN may play a role in the development of sporadic thyroid carcinomas and that one key target of PTEN suppressor activity is represented by the cyclin-dependent kinase inhibitor p27kip1.

Blotting, Northern↗