Cancer Letters

Cancer Letters

Volume 200, Issue 1, 8 October 2003, Pages 85-91
Cancer Letters

Low expression of sodium iodide symporter identifies aggressive thyroid tumors

https://doi.org/10.1016/S0304-3835(03)00392-6Get rights and content

Abstract

A decreased radioiodine uptake is frequently detected in differentiated thyroid carcinomas (DTC) and is associated with high recurrence rate and reduced survival. We investigated the correlation between NIS mRNA expression levels in the primary tumor and patient outcome using a quantitative real-time RT-PCR method. NIS expression was decreased in 17 DTC (21.04±39.66 pg Eq) compared to four autoimune thyroid disease (180.51±92.63 pg Eq) and 14 normal tissues (75.71±66.98 pg Eq) (p<0.0001). The 17 thyroid differentiated carcinoma patients were submitted to surgery complemented by radioiodine ablation and had at least 24 months of follow-up, under levothyroxine continued suppressive therapy. According to their outcome, we could characterize a group of papillary carcinoma patients with aggressive carcinomas, whose NIS mRNA levels were markedly lower than a group with non-aggressive carcinomas (0.62±0.79 versus 54.87±53.79; p<0.005). We suggest that the quantification of NIS mRNA relative levels in the primary tumor may predict poor outcome.

Introduction

Appropriate therapy in differentiated carcinoma patients offers a fairly good prognosis, with patients surviving for many years. Multimodal therapy with surgery followed by radioiodine ablation of residual normal or neoplastic cells is of proven efficacy. Subsequently, patients are managed on levothyroxine to reduce serum levels of the pituitary hormone thyrotropin (TSH) aiming to minimize the growth of any residual tumor. Whole body radioiodine scanning (WBS) and measurement of serum thyroglobulin (Tg) concentration are used to monitor patients. Recurrence develops in 20–40% of patients over decades of follow-up and as well as metastases, are confirmed and treated with radioiodine again [1].

Sodium iodide symporter (NIS) is a membrane glycoprotein that actively mediates iodide uptake on the basolateral membrane of thyroid follicular cells. Because NIS forms the molecular basis for using radioiodine as scintigraphic imaging and therapeutic agent for tissues showing iodine uptake, many investigators have focused on NIS expression and function in thyroid cancer. Indeed, a decreased ability to concentrate radioiodine is frequently detected in most differentiated thyroid carcinomas, with wide variability from one tumor to another. Absolute absence of iodide uptake is found in almost one-third of cases [2]. In addition, loss of differentiation is observed in up to one-third of patients with differentiated thyroid cancer, paralleled by an increase in tumor grading and loss of thyroid-specific functions (thyrotropin receptor, iodine accumulation). Such tumors may no longer be amenable to standard treatment protocols, including TSH suppression and radioiodide therapy [1].

In human thyroid carcinomas, expression of the NIS transcript was detectable, even though at low levels, in most of the tumors examined but extremely reduced or even absent in some of them [3], [4], [5]. Indeed, a recent retrospective immunohistochemical analysis of NIS expression in metastatic differentiated thyroid cancer showed a fair correlation with radioiodine uptake suggesting that NIS expression in the thyroidal primary tumor has substantial ability to predict the behavior of subsequent deposits of metastatic and recurrent cancer regarding iodine trapping and concentration in patients with papillary and follicular thyroid cancers [6]. To investigate this possibility, we carried out a prospective case-control study based on the quantitative evaluation of NIS mRNA relative expression levels in the primary thyroid tumor.

Section snippets

Subjects

The Ethics Committee of the University Hospital—School of Medicine of the State University of Campinas, approved this study and informed written consent was obtained from patients that were consecutively referred to our service because of thyroid nodules. After a fine-needle aspiration biopsy that revealed malignant or suspicious cells, the patients were submitted to a total or near-total thyroidectomy. Thyroid tissue samples from both the index nodule and roughly normal-appearing thyroid

Results

Table 1 summarizes clinical, pathological and follow-up data of the 17 differentiated thyroid carcinoma patients. Using tumor staging at diagnosis and the follow-up data, we could characterize a group A of five PC patients with aggressive carcinomas, that presented local recurrence and/or distant metastasis, in contrast with other six patients (group B) that were disease-free at the end of the period of 24 months observation. The remaining three patients are still under observation and

Discussion

Because most differentiated thyroid carcinomas have an excellent prognosis, some authors have been claiming that these patients are suffering from overtreatment, i.e. total thyroidectomy and ablation of remnants with high doses of radioiodine [9]. Indeed, many surveys reveal relative survival rates up to 93–98% and 85–92% for papillary and follicular carcinoma, respectively [10], [11]. However, the remaining subset of patients develops early recurrence and/or distant metastasis, contributing to

Conclusions

Because radioiodine represents a major diagnostic and therapeutic tool for the management of differentiated thyroid cancer patients, the presence and functional integrity of NIS are prerequisites for iodine concentration. Our results indicate that quantification of NIS mRNA levels could be added to the classic prognostic factors currently used to predict the outcome of patients with differentiated thyroid carcinomas. These data also suggest that patients with primary thyroid tumors with low NIS

References (18)

There are more references available in the full text version of this article.

Cited by (46)

  • Targeting uptake transporters for cancer imaging and treatment

    2020, Acta Pharmaceutica Sinica B
    Citation Excerpt :

    As the major target for the diagnosis and therapy of thyroid cancer, the expression of NIS is crucial for prognosis. Several studies have proven that the NIS protein expression is correlated with I-131 uptake32,33 and thyroid cancer prognosis34. Thus, the modulation or increase of NIS expression could be beneficial for the NIS-mediated imaging and therapy.

  • Expression of the embryonic morphogen Nodal in differentiated thyroid carcinomas: Immunohistochemistry assay in tissue microarray and The Cancer Genome Atlas data analysis

    2014, Surgery (United States)
    Citation Excerpt :

    They revealed that the induction of BRAF activated Notch signaling and, conversely, the inhibition of BRAF decreased Notch signaling. Meanwhile, the BRAF mutation activates the TGF-β/Smad signaling pathways leading to the subsequent repression of the sodium iodide symporter, which is involved in the aggressiveness of thyroid carcinoma.20,21 Considering that Notch regulates Nodal and the Nodal is a member of the TGF-β superfamily,15 the BRAF mutation may induce Nodal expression in PTC.

  • Alpha-lipoic acid induces sodium iodide symporter expression in TPC-1 thyroid cancer cell line

    2012, Nuclear Medicine and Biology
    Citation Excerpt :

    The induction of NIS mRNA by ALA in TPC-1 cell was demonstrated by real-time RT-PCR and Northern blot analyses. Several studies have demonstrated that reduced NIS expression in thyroid cancers is primarily due to reduction in transcription [29–31]. We, using an NIS promoter-reporter construct, showed that ALA increased the promoter activity of the NIS gene, strongly suggesting that ALA acts transcriptionally.

  • The sodium iodide symporter (NIS): Regulation and approaches to targeting for cancer therapeutics

    2012, Pharmacology and Therapeutics
    Citation Excerpt :

    A significant fraction of metastatic thyroid cancer, in the range of 30–40%, does not respond to 131I therapy, even in the presence of an elevated TSH (Maxon & Smith, 1990). Greater NIS expression in thyroid cancer is associated with greater uptake of radioiodide (Castro et al., 2001), as well as a better prognosis (Ward et al., 2003). Increased NIS expression is desired to improve the efficacy of 131I.

  • Synopsis of Pathophysiology in Nuclear Medicine, Second Edition

    2023, Synopsis of Pathophysiology in Nuclear Medicine, Second Edition
View all citing articles on Scopus
View full text