Cargando…
The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma
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 overal...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877516/ https://www.ncbi.nlm.nih.gov/pubmed/29495389 http://dx.doi.org/10.3390/ijms19030655 |
_version_ | 1783310709163032576 |
---|---|
author | Kotlarek, Marta Kubiak, Anna Czetwertyńska, Małgorzata Świerniak, Michał Gierlikowski, Wojciech Kolanowska, Monika Bakuła-Zalewska, Elwira Jhiang, Sissy M. Jażdżewski, Krystian Wójcicka, Anna |
author_facet | Kotlarek, Marta Kubiak, Anna Czetwertyńska, Małgorzata Świerniak, Michał Gierlikowski, Wojciech Kolanowska, Monika Bakuła-Zalewska, Elwira Jhiang, Sissy M. Jażdżewski, Krystian Wójcicka, Anna |
author_sort | Kotlarek, Marta |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5877516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-58775162018-04-09 The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma Kotlarek, Marta Kubiak, Anna Czetwertyńska, Małgorzata Świerniak, Michał Gierlikowski, Wojciech Kolanowska, Monika Bakuła-Zalewska, Elwira Jhiang, Sissy M. Jażdżewski, Krystian Wójcicka, Anna Int J Mol Sci Article 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. MDPI 2018-02-26 /pmc/articles/PMC5877516/ /pubmed/29495389 http://dx.doi.org/10.3390/ijms19030655 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kotlarek, Marta Kubiak, Anna Czetwertyńska, Małgorzata Świerniak, Michał Gierlikowski, Wojciech Kolanowska, Monika Bakuła-Zalewska, Elwira Jhiang, Sissy M. Jażdżewski, Krystian Wójcicka, Anna The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma |
title | The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma |
title_full | The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma |
title_fullStr | The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma |
title_full_unstemmed | The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma |
title_short | The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma |
title_sort | rs2910164 genetic variant of mir-146a-3p is associated with increased overall mortality in patients with follicular variant papillary thyroid carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877516/ https://www.ncbi.nlm.nih.gov/pubmed/29495389 http://dx.doi.org/10.3390/ijms19030655 |
work_keys_str_mv | AT kotlarekmarta thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT kubiakanna thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT czetwertynskamałgorzata thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT swierniakmichał thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT gierlikowskiwojciech thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT kolanowskamonika thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT bakułazalewskaelwira thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT jhiangsissym thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT jazdzewskikrystian thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT wojcickaanna thers2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT kotlarekmarta rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT kubiakanna rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT czetwertynskamałgorzata rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT swierniakmichał rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT gierlikowskiwojciech rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT kolanowskamonika rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT bakułazalewskaelwira rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT jhiangsissym rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT jazdzewskikrystian rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma AT wojcickaanna rs2910164geneticvariantofmir146a3pisassociatedwithincreasedoverallmortalityinpatientswithfollicularvariantpapillarythyroidcarcinoma |