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

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

Monday, 08.10.2018

Treatment of well differentiated thyroid tumors (WDTC) is based on surgery followed by treatment with radioactive iodine (RAI) for the ablation of possible remnants and/or metastases. The success of RAI therapy can be due, essentially to the presence and functionality of the sodium iodine symporter (NIS) in the tumor cell membrane. In The majority of the WDTC maintain the expression and functionality of NIS, which allows the incorporation of radioactive iodine (131I) into the tumor cells, leading to its death. For unknown reasons, some WDTC lose NIS expression/functionality, becoming resistant to radioactive iodine therapy.

In this work, we studied the expression of the gene (SLC5A5) and its protein (NIS) in primary thyroid tumors and evaluated possible associations with pathological, molecular, prognostic and / or therapeutic success.

Our results demonstrated that, although NIS protein expression appears to be very limited, SLC5A5 mRNA expression appears to be a marker of aggressiveness and poor prognosis and, consequently, may help in the prognostic stratification of the patient.

Finally, we also observed that the genetic background of the tumor is of great importance for both the expression of the SLC5A5 gene and for the membrane localization of the NIS protein. The presence of RAS or BRAF and / or TERTp mutations is associated with a significant decrease in the expression of the SLC5A5 gene and the vast majority of the carcinomas that presented NIS expression in the membrane of their cells, were wild type for the aforementioned mutations.

 

Authors and Affiliations:

Catarina Tavares1,2,3, Maria João Coelho1,2,4, Catarina Eloy1,2,3, Miguel Melo1,2,5,6, Adriana Gaspar da Rocha1,2,7, Ana Pestana1,2,3, Rui Batista1,2,3, Luciana Bueno Ferreira1,2,3, Elisabete Rios1,2,3,8,9, Samia Selmi-Ruby10, Bruno Cavadas1,2,4, Luísa Pereira1,2,3, Manuel Sobrinho Simões1,2,3,8,9and Paula Soares1,2,3,8

Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal

Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal;

Medical Faculty of the University of Porto, Porto, Portugal;

Institute of Biomedical Sciences of Abel Salazar (ICBAS), Porto, Portugal

Department of Endocrinology, Diabetes and Metabolism, University and Hospital Center of Coimbra, Coimbra, Portugal;

Medical Faculty, University of Coimbra, Coimbra, Portugal;

Public Health Unit, ACeS Baixo Mondego, Coimbra, Portugal;

Department of Pathology, Medical Faculty of the University of Porto, Porto, Portugal;

Department of Pathology, Hospital de S. João, Porto, Portugal;

10 Inserm UMR-S1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.

 

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.

 

Journal: Endocrine  Connections. 2018 Jan;7(1):78-90. doi: 10.1530/EC-17-0302.

 

Link: https://www.ncbi.nlm.nih.gov/pubmed/29298843