NIS expression in thyroid tumors, relation with prognosis clinicopathological and molecular features

Abstract

Thyroid cancer therapy is based on surgery followed by radioiodine treatment. The incorporation of radioiodine by cancer cells is mediated by sodium iodide symporter (NIS) (codified by the SLC5A5 gene), that is functional only when targeted to the cell membrane. We aimed to evaluate if NIS expression in thyroid primary tumors would be helpful in predicting tumor behavior, response to therapy and prognosis. NIS expression was addressed by qPCR and immunohistochemistry. In order to validate our data, we also studied SLC5A5 expression on 378 primary papillary thyroid carcinomas from The Cancer Genome Atlas (TCGA) database. In our series, SLC5A5 expression was lower in carcinomas with vascular invasion and with extrathyroidal extension and in those harboring BRAFV600E mutation. Analysis of SLC5A5 expression from TCGA database confirmed our results. Furthermore, it showed that larger tumors, with locoregional recurrences and/or distant metastases or harboring RAS, BRAF and/or TERT promoter (TERTp) mutations presented significantly less SLC5A5 expression. Regarding immunohistochemistry, 12/211 of the cases demonstrated NIS in the membrane of tumor cells, those cases showed variable outcomes concerning therapy success, prognosis and all but one were wild type for BRAF, NRAS and TERTp mutations. SLC5A5 mRNA lower expression is associated with features of aggressiveness and with key genetic alterations involving BRAF, RAS and TERTp. Mutations in these genes seem to decrease protein expression and its targeting to the cell membrane. SLC5A5 mRNA expression is more informative than NIS immunohistochemical expression regarding tumor aggressiveness and prognostic features.

The BRAF V600E mutation is a predictor of the effect of radioiodine therapy in papillary thyroid cancer

“…Recent studies indicate that the BRAF V600E mutation can lead to a downregulation of iodine metabolism because the BRAF V600E mutation leads to the continuous activation of the downstream genes of the MAPK pathway, resulting in the decreased expression and abnormal localization of the sodium iodide symporter (NIS). In the case of wild-type BRAF, NIS is primarily located in the thyroid follicular membrane; however, under conditions of the BRAF V600E mutation, NIS cannot be accurately localized to the follicular membrane and is more dispersed in the cytoplasm [40]. Therefore, patients with the BRAF V600E mutation exhibit poor iodine absorption during iodine-131 treatment, which renders the treatment less effective [41], leading to a poor prognosis.…”

mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression

“…To the best of our knowledge, the impact of Torin2 in SLC5A5 mRNA expression or NIS protein function has not been previously addressed. Of note, patients with PTC that developed recurrences and/or distant metastases presented lower levels of SLC5A5 mRNA expression compared to patients without tumor progression [ 30 ]. This information is in line with our present results indicating that mTORC2 (phospho-AKT Ser 473) can be implicated in distant metastization as well as in the regulation of SLC5A5 mRNA expression.…”

Association between TERT promoter mutations and clinical behaviors in differentiated thyroid carcinoma: a systematic review and meta-analysis

“…, 47, 51, 53, 54, 56], 14[11, 14-16, 19, 27, 35, 36, 45, 47, 53, 54, 56, 58], 16 [17, 19, 27, 30, 31, 35-37, 40, 42, 46, 47, 51, 54, 55, 59], 7 [16, 17, 28, 31, 37, 50, 55], 23 [14-17, 19, 27, 30, 31, 35-38, 42, 43, 45, 46, 49-52, 54, 58, 61], 32[11, 14-19, 27-31, 33, 35, 37, 38, 40, 43, 45, 46, 49-56, 58, 59, 61, 62], 15[16,17,28,29,31,32,38,39,43,45,46,50,56,62,63], 24[15- 19, 27-31, 35-40, 42, 43, 45, 46, 50, 51, 54, 56],19 …”