NIS and Thyroid Cancer

As previously mentioned, the treatment of patients with WDTC includes three modalities: thyroidectomy, radioiodine (131I) ablation, and TSH suppression. Unfortunately, about 25% of WDTCs are initially resistant and about 50% of recurrent thyroid cancers are resistant to 131I treatment. These patients have a worse prognosis, and many studies have attempted to enhance radioiodine uptake in thyroid cancer cells in such patients. 1,2'34'37'3S

Since the discovery of the NIS gene, much attention has been focused on the symporter because it is a marker for differentiation and also the mechanism by which radioactive iodide therapy works. Thyroid diseases directly affect the function of the NIS symporter. Three mechanisms, as previously stated, have been proposed for poor iodide uptake in thyroid carcinoma: (1) NIS gene mutations,39 (2) suppression of the NIS gene expression,6,39"44 and (3) post-transcriptional modifications of the NIS protein.24'26

Congenital ITD is an infrequent autosomal recessive condition caused by mutations in the NIS gene. The clinical picture consists of hypothyroidism, goiter, low thyroid iodide uptake, and low saliva-to-plasma iodide ratio. The incidence of ITD is 1 per 4000 neonates. It has an irreversible effect on the growth and development of the neonate, leading to cretinism. Mutations in thyroid-specific molecules such as thyroid peroxidase, thyroglobulin, and TSHR have been identified.45"47 NIS mutations have also been reported in congenital hypothyroidism resulting in the absence of the functional NIS symporter. Kosugi and coworkers39 reported that a T354P NIS gene mutation was found in seven Japanese patients from five unrelated families. To date, approximately 60 cases of ITD belonging to 33 families have been reported. Twenty-seven cases from 13 families studied have been shown to have NIS gene mutations.12'39 48 50

Thyroid cancer has not been shown to involve the mutations seen in congenital ITD. Russo and colleagues51 performed direct sequencing of NIS cDNA from five papillary and two follicular thyroid cancers and found no mutations in the NIS gene. The proposed mechanism of reduced radioactive uptake in thyroid cancer has been associated with decreased expression of the NIS gene. Bidart and associates52 showed that NIS protein immunostaining is increased in Graves' disease and reduced in Hashimoto's and thyroid cancer. Our own studies have confirmed that NIS gene expression is increased in Graves' disease and hyperactive adenomas and reduced in Hashimoto's disease. Also, expression of the NIS symporter is reduced in papillary, medullary, and follicular thyroid cancers. Schmutzler53 found that the redifferentiation effect of retinoic acid in thyroid cancer cells is associated with increased NIS gene expression.

NIS gene expression not only may be deceased in thyroid cancer but also may affect post-transcriptional targeting of the NIS protein. Saito and colleagues24 showed that 7 of 17 papillary thyroid carcinomas overexpressed the NIS gene, but the NIS protein was located in the cytoplasm and not on the cell membrane. In contrast, NIS protein expression was barely detected in the paratumoral normal tissue. Contrary to the results of Saito and colleagues, several investigators have found absent or intermediate expression staining of the NIS protein in differentiated thyroid cancer.54 55

Extracellular

FIGURE 37-2. Schematic model of the human sodium-iodide symporter, which represents an intrinsic membrane protein with 13 transmembrane and 14 extramembranous domains and 3 potential N-linked glycosyla-tion sites. ExM = Extramembranous domains.

1 ■ Sequence numbers t - Transmembrane domains 1 - ExM domains A N-linked glycosylate sites

Intracellular

Extracellular

Intracellular

Loss of polarization and impaired membrane targeting of other membrane proteins have been described in malignant thyroid cancer. The epidermal growth factor receptor, as detected by immunohistochemistry, was overexpressed and localized not only pericellularly but also intracellularly rather than exclusively localized on the basolateral membrane as in normal cells.

NIS must be expressed, targeted, and retained in the appropriate plasma membrane surface in polarized epithelial cells for active iodide transport to occur. TSH regulates NIS distribution between the plasma membrane and intracellular membrane compartments. In thyroid cancer cells, iodide transport can still be present even in the absence of cell polarization, but targeting to and retention in the plasma membrane remain essential if active iodide transport is to take place. Therefore, elucidating the mechanisms involved in proper targeting and retention of NIS at the plasma membrane is essential to enhancing iodide uptake in thyroid cancer cells.

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