Human thyrotropin receptor gene: Expression in thyroid tumors and correlation to markers of thyroid differentiation and dedifferentiation

doi:10.1016/0303-7207(91)90018-N

Molecular and Cellular Endocrinology

Volume 82, Issue 1, November 1991, Pages R7-R12

https://doi.org/10.1016/0303-7207(91)90018-N Get rights and content

Abstract

Human thyrotropin (TSH) receptor steady-state transcript levels were analyzed by Northern blot analysis in thyroids of patients with thyroid carcinoma, with hyperfunctioning adenoma and in normal controls. In control tissue and benign tumors expression levels of TSH receptor mRNA were high whereas in anaplastic carcinomas no normal TSH receptor mRNA was detected. In papillary and follicular tumors it varied from normal to markedly reduced levels. Thyroid peroxidase (TPO) and thyroglobulin (Tg) mRNA were strongly expressed in normal tissue and in hyperfunctioning adenomas but were completely lost in all anaplastic tumors. In papillary tumors expression of TPO and Tg mRNA varied from normal to a complete loss of expression of either TPO, Tg or both. Tg and TPO steady-state expression did not correlate to TSH receptor transcript levels. C-myc mRNA was highly expressed in anaplastic carcinomas, very variable in normal controls and in differentiated thyroid tumors and low in hyperfunctioning adenomas.

In summary, TSH receptor mRNA is persistently expressed in all differentiated thyroid tissues and tumors but lost in undifferentiated carcinomas. Its persistence far along the transformation pathway further supports the concept that this gene which inserts the thyrocytes in the physiological regulatory network is almost constitutively expressed in this cell.

References (33)

M.T. Berlingieri et al.
Biochem. Biophys. Res. Commun.
(1990)
I.D. Hay
Endocrinol. Metab. Clin. N. Am.
(1990)
F. Libert et al.
Biochem. Biophys. Res. Commun.
(1989)
Y. Nagayama et al.
Biochem. Biophys. Res. Commun.
(1989)
S. Reuse et al.
Exp. Cell Res.
(1990)
G. Sand et al.
Eur. J. Cancer
(1976)
R. Aasland et al.
Br. J. Cancer
(1988)
Y. Abe et al.
J. Clin. Endocrinol. Metab.
(1981)
V.E. Avvedimento et al.
J.L. Berge-LeFranc et al.
Cancer
(1985)

H. Brocas et al.

FEBS Lett.

(1982)

K.D. Burman et al.

Horm. Metab. Res. Suppl.

(1987)

P. Carayon et al.

J. Clin. Endocrinol. Metab.

(1980)

T.C. Chang et al.

Clin. Endocrinol.

(1988)

M. Chirgwin et al.

Biochemistry

(1979)

H. Dralle et al.

Acta Endocrinol.

(1985)

Cited by (143)

Epigenetic Control in Human Normal Follicular Thyroid Cells and in Thyroid Carcinoma
2016, Medical Epigenetics
Inhibition of miR-146b expression increases radioiodine-sensitivity in poorly differential thyroid carcinoma via positively regulating NIS expression
2015, Biochemical and Biophysical Research Communications
Citation Excerpt :
Moreover, it has been reviewed the tremendous potential of miRNAs for use in the diagnosis and prognosis of thyroid tumors, including miR-196, miR-146b, miR-155 and so on [8–10]. Differentiated thyroid cells express a number of differentiation markers such as thyroglobulin (Tg), thyroperoxidase (TPO) and the Na+/I− symporter (NIS), that are responsible for iodine uptake, synthesis of thyroid hormones and the differentiated thyroid phenotype [11]. Studies have revealed that decreased TSH receptor (TSHR) expression correlate with FTC-133 ongoing dedifferentiation after 131I radiation, while TSHR transfection can also improve the expression of thyroid-specific molecules, including TSHR, NIS and TPO, and radioiodine uptake (RAIU) [12,13].
Dedifferentiated thyroid carcinoma (DTC) with the loss of radioiodine uptake (RAIU) is often observed in clinical practice under radioiodine therapy, indicating the challenge for poor prognosis. MicroRNA (miRNA) has emerged as a promising therapeutic target in many diseases; yet, the role of miRNAs in RAIU has not been generally investigated. Based on recent studies about miRNA expression in papillary or follicular thyroid carcinomas, the expression profiles of several thyroid relative miRNAs were investigated in one DTC cell line, derived from normal DTC cells by radioiodine treatment. The top candidate miR-146b, with the most significant overexpression profiles in dedifferentiated cells, was picked up. Further research found that miR-146b could be negatively regulated by histone deacetylase 3 (HDAC3) in normal cells, indicating the correlation between miR-146b and Na⁺/I⁻ symporter (NIS)-mediated RAIU. Fortunately, it was confirmed that miR-146b could regulate NIS expression/activity; what is more important, miR-146b interference would contribute to the recovery of radioiodine-sensitivity in dedifferentiated cells via positively regulating NIS. In the present study, it was concluded that NIS-mediated RAIU could be modulated by miR-146b; accordingly, miR-146b might serve as one of targets to enhance efficacy of radioactive therapy against poorly differential thyroid carcinoma (PDTC).
Thyroid Regulatory Factors
2015, Endocrinology: Adult and Pediatric
Targeting the thyroid gland with thyroid-stimulating hormone (TSH)-nanoliposomes
2014, Biomaterials
Citation Excerpt :
TSHr expression is maintained in most thyroid pathologies, including benign and malignant tumors [18–23]. More importantly, the receptor is also present in the majority of less differentiated and more aggressive tumors [18–23], making it an optimal target for the delivery of chemotherapeutics. 1,2-dipalmitoyl-sn-glycero-3-phospocholine monohydrate (DPPC) and N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-mPEG2000) were purchased from Genzyme (Suffolh, UK).
Various tissue-specific antibodies have been attached to nanoparticles to obtain targeted delivery. In particular, nanodelivery systems with selectivity for breast, prostate and cancer tissue have been developed. Here, we have developed a nanodelivery system that targets the thyroid gland. Nanoliposomes have been conjugated to the thyroid-stimulating hormone (TSH), which binds to the TSH receptor (TSHr) on the surface of thyrocytes. The results indicate that the intracellular uptake of TSH-nanoliposomes is increased in cells expressing the TSHr. The accumulation of targeted nanoliposomes in the thyroid gland following intravenous injection was 3.5-fold higher in comparison to untargeted nanoliposomes. Furthermore, TSH-nanoliposomes encapsulated with gemcitabine showed improved anticancer efficacy in vitro and in a tumor model of follicular thyroid carcinoma. This drug delivery system could be used for the treatment of a broad spectrum of thyroid diseases to reduce side effects and improve therapeutic efficacy.
The current role of targeted therapies to induce radioiodine uptake in thyroid cancer
2014, Cancer Treatment Reviews
Citation Excerpt :
TPO in TC is suppressed at both the mRNA and protein level in some studies while according to others it is not altered [27,28]. Levels of Tg mRNA varying from normal to complete loss in TC are seen [29,30]. Decreases in Tg were not related to dys-regulation of pathways common in TC [31].
Targeted therapy pinpointing specific alteration in cancer cells has gained an important role in the treatment of cancer. Compounds that re-induce thyroid-specific functions could be particularly useful in differentiated thyroid cancers by rendering them susceptible to radioiodine treatment, which is relatively specific and has few adverse effects. This review describes the rationale for radioiodine treatment, considering the targets of compounds with differentiation-inducing effects, and the impact of these drugs on the expression of thyroid-specific proteins and on iodine-uptake. We survey the results from the clinical trials thus far performed. We conclude that although retinoids, thiazolidinediones, histone deacetylase inhibitors and DNA methyltransferase inhibitors do increase the expression of thyroid-specific proteins, their clinical efficacy is limited. The relatively low rate of remissions in clinical trials with re-differentiating compounds could be due to low levels of the target, heterogeneity of iodine uptake into the tumor, poor correlation of radioiodine uptake and clinical remission, and/or the slow onset of the therapeutic effect. Although the mode of action is not clear, the combination of tyrosine kinase inhibitors and RAI treatment could improve clinical responses in non-radioiodine avid metastatic thyroid carcinoma.
Coexistence of Graves' disease, papillary thyroid carcinoma and unilateral benign struma ovarii: Case report and review of the literature
2013, Metabolism: Clinical and Experimental
Struma ovarii is a rare cause of hyperthyroidism, while coexistence with Graves’ disease has been scarcely reported.
We report a patient with Graves’ disease and unilateral benign functioning struma ovarii, accompanied by ascites, pleural effusion and elevated cancer antigen-125 (CA-125) levels. In subsequent thyroidectomy, incidental papillary thyroid carcinoma was also identified. The functionality of struma ovarii tissue in our patient was supported by the immunohistochemical identification of TSH receptors (TSHR), which may stimulate growth and thyroid hormone production in the presence of circulating TSHR stimulating antibodies (TSHR-Ab).
A systematic review of reported cases of coexistent Graves’ disease and struma ovarii was performed.
The diagnosis of struma ovarii may be masked by Graves’ disease and, therefore, be delayed for several years. Furthermore, ascites, pleural effusion and increased CA-125 may result from a benign struma ovarii. The presence of TSHR in the struma ovarii tissue along with their absence in the surrounding ovarian tissue indirectly suggests that struma ovarii is functional. It is unclear whether TSHR-Ab play a role in the development of thyroid carcinomas in such patients.

View all citing articles on Scopus

View full text

Rapid paperHuman thyrotropin receptor gene: Expression in thyroid tumors and correlation to markers of thyroid differentiation and dedifferentiation

Abstract

Biochem. Biophys. Res. Commun.

Endocrinol. Metab. Clin. N. Am.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Exp. Cell Res.

Eur. J. Cancer

Br. J. Cancer

J. Clin. Endocrinol. Metab.

Cancer

FEBS Lett.

Horm. Metab. Res. Suppl.

J. Clin. Endocrinol. Metab.

Clin. Endocrinol.

Biochemistry

Acta Endocrinol.

Rapid paper
Human thyrotropin receptor gene: Expression in thyroid tumors and correlation to markers of thyroid differentiation and dedifferentiation