endothelin-1 and Thyroid-Neoplasms

The endothelin (EDN) axis (EDN1 and EDN1 receptor A, EDNRA) is involved in cellular growth, differentiation, invasiveness, and tumor progression in several cancers. We wanted to examine the possible impact of single nucleotide polymorphisms (SNPs) of EDN1 and EDNRA genes on papillary thyroid cancer (PTC) development and general characteristics of PTC. Study population consist of 113 PTC patients and 185 controls. EDN1 (G5665T, T-1370G) and EDNRA (C TT70G, G-231A) SNPs were investigated by real-time PCR. The GG genotype of EDNRA + 70 SNP was associated with threefold increased PTC risk (p = 0.01), and the combined CG + GG genotype was 2.48 fold higher among PTC patients compared to controls. The variant EDNRA - 231 allele was overrepresented in PTC patients according to controls (p = 0.05). The combined GT + TT genotype of EDN1 5665 SNP was related with late (age after 40 years) PTC onset (p = 0.04), and was more prominent among male patients with PTC according to females (p = 0.03). No significant associations between PTC and - 1370 SNP were found. There were no relationships between laboratory parameters and investigated polymorphisms. The EDNRA + 70 SNP was associated with PTC development. The EDN1 5665 SNP was linked with increased risk for late PTC onset and was more prominent among male patients with PTC.

Topics: Adult; Aged; Alleles; Endothelin-1; Endothelins; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Endothelin A; Receptors, Endothelin; Risk Factors; Thyroid Cancer, Papillary; Thyroid Neoplasms

The endothelin axis is a group of signaling molecules and their receptors that have been implicated in vascularization of cancers, with their expression being observed to change in different cancer types. In this research, we examined the expression of endothelin 1 and endothelin receptor A at the protein and messenger RNA (mRNA) levels in 123 papillary thyroid carcinomas and 40 matched lymph nodes with metastatic papillary thyroid carcinomas. We found altered endothelin axis mRNA expression in several clinicopathologic parameters with increased endothelin 1 expression in thyroid papillary carcinoma showing stromal calcification, cancers in men, and primary cancers with lymph node metastases. Increased endothelin receptor A mRNA expression was noted in the larger cancers. There is a significant correlation between expression of endothelin receptor A and endothelin 1 in papillary thyroid carcinoma. Both endothelin receptor A and endothelin 1 mRNA expressions were significantly higher in metastatic carcinoma in the lymph node than in primary thyroid cancer. The metastatic carcinoma in the lymph node had increased expression compared with matched primary thyroid carcinoma. Expressions of endothelin 1 and endothelin receptor A were also documented as being high at the protein level. Our results indicate that in thyroid cancer, endothelin 1 and endothelin receptor A are associated with growth in advanced stages and lymph node metastases, likely through known angiogenic linkages. Targeting the endothelin axis may be useful in planning angiogenesis therapy for thyroid cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Australia; Biomarkers, Tumor; Carcinoma, Papillary; Cohort Studies; Endothelin-1; Female; Gene Expression Regulation, Neoplastic; Humans; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Receptor, Endothelin A; RNA, Messenger; RNA, Neoplasm; Thyroid Gland; Thyroid Neoplasms; Young Adult

Endothelin-1 (ET-1) may play a role in carcinogenesis. ET-1 axis is overexpressed in thyroid carcinoma. We investigated the expression and the production of ET-1 by thyroid cancer cells as well as the effect of ET-1 receptor antagonism on cell proliferation.. Human papillary and follicular thyroid carcinoma cell lines were cultured.. (i) Prepro-ET-1, ET-1 receptors (ETA R and ETB R) and ET-1 converting enzyme (ECE) by reverse transcriptase polymerase chain reaction (RT-PCR); (ii) the presence of ETA R by western blot; (iii) ET-1 concentrations in medium by an enzyme immunometric assay; (iiii) the proliferation of cells by BrdU and tritiated thymidine incorporation.. RT-PCR detected the presence of mRNA for prepro-ET-1, ETA R and ECE in papillary and follicular carcinoma cells. ETB R was only expressed by follicular cells. ETA R was also detected in both cell types by western blot. Measurements of ET-1 concentrations demonstrated a secretion of active ET-1 by the cells. ETA R antagonism with atrasentan reduced cell proliferation by 16% in papillary carcinoma cells (P < 0.05) and by 51% in follicular carcinoma cells (P < 0.001).. Papillary and follicular carcinoma cells express all components of the ET-1 axis. ETA R antagonism exerts antiproliferative effects, which opens up new therapeutic perspectives in thyroid carcinoma.

Topics: Adenocarcinoma, Follicular; Aspartic Acid Endopeptidases; Atrasentan; Blotting, Western; Bromodeoxyuridine; Carcinoma, Papillary; Cell Line, Tumor; Cell Proliferation; Endothelin A Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Humans; Immunoradiometric Assay; Metalloendopeptidases; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thymidine; Thyroid Neoplasms

Nitric oxide (NO) and endothelin-1 (ET-1) are involved in carcinogenesis. Overexpression of the ET-1 axis has been demonstrated in papillary thyroid carcinoma (PTC). This study investigated the expression of NO synthases (NOS) and their relationship with expression of ET-1 and angiogenic markers in PTC.. Expression of NOS, angiogenic markers [vascular endothelial growth factor (VEGF), angiopoietin-1 and angiopoietin-2] and their receptors was studied in surgical thyroid samples obtained from 22 patients aged 15-68 years. Three groups were constituted: normal thyroid (n = 5), Hashimoto's thyroiditis (n = 9) and PTC (n = 8).. Immunohistochemistry disclosed NOS2 and NOS3 immunoreactivity in PTC cells, the percentage of positive cells being greater than normal (P < 0.02). Real-time quantitative polymerase chain reaction (RTQ-PCR) showed that NOS2 and NOS3 mRNA levels were, respectively, increased (P < 0.02) by 2.6 +/- 0.6 and 4.2 +/- 1.1 times in PTC. RTQ-PCR demonstrated that VEGF, its receptors VEGFR-1 and VEGFR-2, and angiopoietin-2 and its receptor (Tie2) were also overexpressed (P < 0.05) in PTC. Correlations were found between ET-1 expression and that of NOS2, angiopoietin-1 and -2 (P < 0.05). NOS2 mRNA levels also correlated with those of NOS3 and angiopoietin-2 (P < 0.05). In thyroiditis, NOS2 immunoreactivity was observed in inflammatory cells whereas NOS2 mRNA levels were 12.1 +/- 1.6 times higher than normal (P < 0.005).. This study revealed an activation of the NO pathway in thyroid carcinoma, which is interrelated to the ET-1 axis, both systems being overexpressed in concert with angiogenic factors. This global system might play a role in carcinogenesis and constitutes a potential target for anticancer therapy.

Topics: Adolescent; Adult; Aged; Angiopoietin-1; Angiopoietin-2; Carcinoma, Papillary; Case-Control Studies; Endothelin-1; Female; Hashimoto Disease; Humans; Immunohistochemistry; Male; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Receptor, TIE-2; RNA, Messenger; Thyroid Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Topics: Adult; Calcitonin; Carcinoma, Medullary; Endothelin-1; Female; Humans; Male; Receptors, Endothelin; RNA, Messenger; RNA, Neoplasm; Thyroid Neoplasms

Since its discovery in 1988, endothelin has initiated intense research activities, showing that it was not only a vasoconstrictor and mitogenic peptide produced by the vascular endothelium but also a ubiquitous molecule with various functions. A production of ET-1 has been evidenced in the thyroid and ET-1 receptors have been detected on thyroid cells. Produced by the vessels and the thyrocytes, ET-1 could exert paracrine and/or autocrine effects on vascular tone in the thyroid and on some functions of thyrocytes. Because of proliferative effects, its role in thyroid diseases could involve goitrogenesis and carcinogenesis. Using thyroid samples obtained at the time of surgery, we demonstrated increased expressions of ET-1 and its mitogenic receptor ET(A) in papillary carcinoma of the thyroid. Immunohistochemical studies and real-time quantitative polymerase chain reaction (RTQ-PCR) were used for this purpose. As demonstrated in other cancers, activation of endothelin axis, particularly through ET(A) receptor could contribute to cell proliferation, cell survival, angiogenesis and the development of bone metastases. ET-1 is also a proinflammatory mediator and we demonstrated an overexpression of ET-1 and of its receptor ET(A) in Hashimoto's thyroiditis. This suggests a role of ET-1 as a cytokine. In nodular goitre, ET-1 is also overexpressed but to a lesser extent than in papillary thyroid carcinoma and in Hashimoto's thyroiditis. Finally, antagonists of ET-1 receptors are currently under development and could be used in man. They could open new therapeutic perspectives in the treatment of metastatic thyroid carcinoma.

Topics: Carcinoma, Papillary; Endothelin-1; Humans; Receptor, Endothelin A; Thyroid Neoplasms

Since the isolation of endothelin-1 (ET-1) in 1988, there has been tremendous interest in the pathophysiological roles of ET-1 as a vasoconstrictive and mitogenic peptide. Whereas ET-1 is mainly released by vascular endothelial cells, it also proved to be produced by various tissues including the thyroid. Because of its mitogenic properties in malignancy and its role as an inflammatory modulator, ET-1 could be involved in thyroid carcinogenesis and thyroiditis.. Studies were performed in human thyroid samples obtained at the time of surgery from 39 men and women aged 15-72 years. Thyroid samples were classified in four groups according to conventional histology: normal thyroid (n = 7) papillary thyroid carcinoma (n = 12), Hashimoto's thyroiditis (n = 9) and benign nontoxic nodular goitres (n = 11). Immunohistochemistry and real-time quantitative polymerase chain reaction were used to determine the expression of ET-1 and its receptors (ETAR and ETBR).. ET-1 and ETAR mRNA levels were, respectively, 3.8 +/- 1.3 and 4.1 +/- 1.5 times greater (P < 0.001) in papillary thyroid carcinoma than in normal thyroid. Expression of ETBR was unaltered. In Hashimoto's thyroiditis, ET-1 and ETAR were also overexpressed (P < 0.005). Furthermore, immunohistochemistry demonstrated a greater percentage of ET-1-positive follicular cells in these conditions (P < 0.001). In nodular goitres, the expression was increased by 1.7 +/- 0.7 times (P < 0.05) but expression of receptors remained unchanged.. ET-1 and ETAR overexpression observed in thyroid carcinoma suggest a mitogenic role of ET-1 that theoretically could be countered by ETAR antagonists. ET-1 and ETAR overexpression in thyroiditis supports a role of ET-1 in the inflammatory process.

Topics: Adolescent; Adult; Aged; Carcinoma, Papillary; Endothelin-1; Female; Goiter, Nodular; Humans; Immunohistochemistry; Male; Middle Aged; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Neoplasms; Thyroiditis, Autoimmune