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Int. J. Mol. Sci. 2018, 19(3), 655; https://doi.org/10.3390/ijms19030655

The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma

1
Genomic Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland
2
Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland
3
Department of Nuclear Medicine & Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland
4
Department of Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland
5
Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA
*
Author to whom correspondence should be addressed.
Received: 27 January 2018 / Revised: 18 February 2018 / Accepted: 20 February 2018 / Published: 26 February 2018
(This article belongs to the Collection Advances in Molecular Oncology)
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Abstract

Aberrant expression of the sodium-iodide symporter (NIS) and the resistance to post-operative radioactive iodide treatment is a crucial cause of higher mortality of some thyroid cancer patients. In this study, we analyzed the impact of miR-146a on the expression and function of NIS and on the overall survival of thyroid cancer patients. The study included 2441 patients (2163 women; 278 men); including 359 cases with follicular variant of papillary thyroid carcinoma (fvPTC). miR:NIS interactions were analyzed in cell lines using in vivo binding and inhibition assays and radioactive iodine uptake assays. Tumor/blood DNA was used for rs2910164 genotyping. Overall survival was assessed retrospectively. In the results, we showed that miR-146a-3p directly binds to and inhibits NIS. Inhibition of miR-146a-3p restores the expression and function of NIS, increasing radioactive iodine uptake. Rs2910164 functional variant within miR-146a-3p is associated with increased overall mortality among fvPTC female patients. The deaths per 1000 person-years were 29.7 in CC carriers vs. 5.08 in GG/GC-carriers (HR = 6.21, p = 0.006). Higher mortality of CC vs. GG/GC carriers was also observed in patients with lower clinical stage (HR = 22.72, p < 0.001), smaller tumor size (pT1/pT2) (HR = 25.05, p < 0.001), lack of extrathyroidal invasion (HR = 9.03, p = 0.02), lack of nodular invasion (HR = 7.84, p = 0.002), lack of metastases (HR = 6.5, p = 0.005) and older (age at diagnosis >50 years) (HR = 7.8, p = 0.002). MiR-146a-3p underwent somatic mutations in 16.1% of analyzed specimens, mainly towards the deleterious C allele. In this report we propose a novel molecular marker of the clinical outcome of fvPTC patients. Rs2910164 increases the overall mortality with inhibition of NIS and disruption of radioiodine uptake as a possible mechanism. View Full-Text
Keywords: microRNA; miRNA-146a; rs2910164; papillary thyroid carcinoma (PTC); thyroid carcinoma microRNA; miRNA-146a; rs2910164; papillary thyroid carcinoma (PTC); thyroid carcinoma
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Kotlarek, M.; Kubiak, A.; Czetwertyńska, M.; Świerniak, M.; Gierlikowski, W.; Kolanowska, M.; Bakuła-Zalewska, E.; Jhiang, S.M.; Jażdżewski, K.; Wójcicka, A. The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma. Int. J. Mol. Sci. 2018, 19, 655.

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