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

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.

Fine mapping of 14q13 reveals novel variants associated with different histological subtypes of papillary thyroid carcinoma

“…33 As recently shown PTC-associated SNP rs2910164 increases overall mortality in patients with fvPTC but not in cPTC suggesting heterogeneity of PTC in terms of genetic background. 34 Our data show that the 14q13 locus harbors rs1632250, rs28397092 rs368187, rs1863347 and rs1755787 that are associated with different histological subtypes of PTC and this association is independent of the first two reported GWAS SNPs present in the region. The strongest association was observed for rs368187.…”

“…This suggests that the genetic background of PTC might be different across its histological subtypes, which could produce different clinical features . As recently shown PTC‐associated SNP rs2910164 increases overall mortality in patients with fvPTC but not in cPTC suggesting heterogeneity of PTC in terms of genetic background …”

The key microRNA on lipid droplet formation during adipogenesis from human mesenchymal stem cells

“…Except for the known miRNA hsa‐miR‐1908 regulating adipogenesis, all five miRNAs, including hsa‐miR‐146a‐3p, hsa‐miR‐4495, hsa‐miR‐4663, hsa‐miR‐6069, and hsa‐miR‐675‐3p, are the latest potential biomarkers for LD formation, targeting ACSL1, APOB, METTL7A, PLIN1, and PLIN4. hsa‐miR‐146a‐3p functioned in macrophage differentiation and polarized activation processes of bone marrow–derived macrophages (Zhang, Zhang, Zhong, Suo, & Lv, ); downregulated the target RasGAP‐p120 enhancing tube formation in endothelial cells in cardiac progenitor cells (CPCs; Barile et al, ); significantly reduced antiphospholipid antibody‐induced trophoblast IL‐8 secretion (Gysler et al, ); differentially regulated in autoimmune lymphoproliferative syndrome (ALPS) due to FAS mutation (ALPS‐FAS) (Marega, Teocchi, & Dos Santos Vilela, ); cardioprotective in CPC‐derived exosomes (Barile, Moccetti, Marbán, & Vassalli, ); promoting bladder cancer migration, invasion, metastasis, and growth by regulating PTTG1 (Xiang et al, ); reduced in microvesicles (0.1–1.0 μm in diameter) released by human coronary artery smooth muscle cells (de Gonzalo‐Calvo et al, ); exosomal accumulation increased by reticuloendotheliosis virus and avian leukosis virus subgroup J synergistically (Zhou et al, ); associated with increased overall mortality in patients with follicular variant papillary thyroid carcinoma (Kotlarek et al, ) and with rheumatoid arthritis (Bogunia‐Kubik et al, ), and a novel regulator of fine particulate matter (PM2.5) exerted M1 polarization by targeting SIRT1 (Zhong et al, ). hsa‐miR‐4663 was the potential biomarkers for glaucoma (Hindle et al, ).…”

Identification of a Novel, Diagnostic microRNA Signature in Papillary Thyroid Cancer

“…For instance, miR-144-3p promotes tumor growth and metastasis of papillary thyroid cancer cells by targeting the expression of PAX8 and WWTR1 [15,16]. A genetic polymorphism in the sequence of miR-146a-3p is associated with worse prognosis of patients with papillary thyroid cancer [17]. Moreover, upregulation of miR-340-5p promotes thyroid cancer progression by targeting and downregulating BMP4 [18].…”