Correlation between the Loss of Thyroglobulin Iodination and the Expression of Thyroid-Specific Proteins Involved in Iodine Metabolism in Thyroid Carcinomas

Abstract

Progress in biotechnology has provided useful tools for tracing proteins involved in thyroid hormone synthesis in vivo. Mono- or polyclonal antibodies are now available to detect on histological sections the Na(+)/I(-) symporter (NIS) at the basolateral pole of the cell, the putative iodide channel (pendrin) at the apical plasma membrane, thyroperoxidase (TPO), and members of the NADPH-oxidase family, thyroid oxidase 1 and 2 (ThOXs), part of the H(2)O(2)-generating system. The aim of this study was to correlate thyroglobulin (Tg) iodination with the presence of these proteins. Tg, T(4)-containing Tg, NIS, pendrin, TPO, ThOXs, and TSH receptor (TSHr) were detected by immunohistochemistry on tissue sections of normal thyroids and various benign and malignant thyroid disorders. Tg was present in all cases. T(4)-containing Tg was found in the adenomas, except in Hurthle cell adenomas. It was never detected in carcinomas. NIS was reduced in all types of carcinomas, whereas it was detected in noncancerous tissues. Pendrin was not expressed in carcinomas, except in follicular carcinomas, where weak staining persisted. TPO expression was present in insular, follicular carcinomas and in follicular variants of papillary carcinomas, but in a reduced percentage of cells. It was below the level of detection in papillary carcinomas. The H(2)O(2)-generating system, ThOXs, was found in all carcinomas and was even increased in papillary carcinomas. Its staining was apical in normal thyroids, whereas it was cytoplasmic in carcinomas. The TSHr was expressed in all cases, but the intensity of the staining was decreased in insular carcinomas. In conclusion, our work shows that all types of carcinomas lose the capacity to synthesize T(4)-rich, iodinated Tg. In follicular carcinomas, this might be due to a defect in iodide transport at the basolateral pole of the cell. In papillary carcinomas, this defect seems to be coupled to an altered apical transport of iodide and probably TPO activity. The TSHr persists in virtually all cases.

Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice

“…In both RET/PTC3 and E7 transgenic mouse thyroids, the ability to concentrate radioiodide is generally reduced as in human thyroid carcinomas (Gérard et al, 2003).…”

“…This can be correlated with data in the human PTC. It could be due to an increased intracellular NIS misexpression (Saito et al, 1998;Wapnir et al, 2003;Riesco-Eizaguirre and Santisteban, 2006), to conformational changes (Gérard et al, 2003) or to the non maturation of hNIS (Trouttet-Masson et al, 2004).…”

A molecular analysis and long-term follow-up of two siblings with severe congenital hypothyroidism carrying the IVS30+1G>T intronic thyroglobulin mutation

“…Previous reports have shown predominantly intracellular localization of NIS protein in thyroid tumors (30)(31)(32).…”

Targeting the TSH receptor in thyroid cancer

“…Several studies have found that TSHR expression closely parallels other markers of differentiation, such as thyroglobulin and thyroperoxidase (Hoang-Vu et al 1992, Elisei et al 1994, Park et al 2000. However, evidence from a number of studies of resected thyroid tissue suggests that TSHR is more persistently expressed than other differentiation markers, including NIS and thyroglobulin proteins , Lazar et al 1999, Gerard et al 2003, indicating not only that TSHR may remain an important signaling pathway for cellular growth but also its utility as a conserved therapeutic target. Further in vivo evidence of continued TSHR expression in the absence of NIS is provided by a study of 63 patients with metastatic DTC, and no radioactive iodine uptake on whole body scan, who underwent 18 F-fludeoxyglucose positron emission tomography ( 18 F-FDG-PET) both under basal conditions and after rhTSH stimulation (Leboulleux et al 2009).…”