microRNA-339-5p modulates Na+/I− symporter-mediated radioiodide uptake

Abstract

Na+/I− symporter (NIS)-mediated radioiodide uptake (RAIU) serves as the basis for targeted ablation of thyroid cancer remnants. However, many patients with thyroid cancer have reduced NIS expression/function and hence do not benefit from radioiodine therapy. microRNA (miR) has emerged as a promising therapeutic target in many diseases; yet, the role of miRs in NIS-mediated RAIU has not been investigated. In silico analysis was used to identify miRs that may bind to the 3′UTR of human NIS (hNIS). The top candidate miR-339-5p directly bound to the 3′UTR of hNIS. miR-339-5p overexpression decreased NIS-mediated RAIU in HEK293 cells expressing exogenous hNIS, decreased the levels of NIS mRNA, and RAIU in transretinoic acid/hydrocortisone (tRA/H)-treated MCF-7 human breast cancer cells as well as thyrotropinstimulated PCCl3 rat thyroid cells. Nanostring nCounter rat miR expression assay was conducted to identify miRs deregulated by TGFβ, Akti-1/2, or 17-AAG known to modulate RAIU in PCCl3 cells. Among 38miRs identified, 18 were conserved in humans. One of the 18 miRs, miR-195, was predicted to bind to the 3′ UTR of hNIS and its overexpression decreased RAIU in tRA/H-treated MCF-7 cells. miR-339-5p was modestly increased inmost papillary thyroid carcinomas (PTCs), yet miR-195 was significantly decreased in PTCs. Interestingly, the expression profiles of 18 miRs could be used to distinguish most PTCs from nonmalignant thyroid tissues. This is the first report, to our knowledge, demonstrating that hNIS-mediated RAIU can be modulated by miRs, and that the same miRs may also play roles in the development or maintenance of thyroid malignancy. Accordingly, miRs may serve as emerging targets to halt the progression of thyroid cancer and to enhance the efficacy of radioiodine therapy.

The miR-146b-3p/PAX8/NIS Regulatory Circuit Modulates the Differentiation Phenotype and Function of Thyroid Cells during Carcinogenesis

“…We demonstrate for the first time that NIS is posttranscriptionally modulated by miRNAs in thyroid cancer. Very recently, it has been shown that miR-339 modulates NIS expression in rat normal thyroid cells (37), yet this miRNA has not been shown to be deregulated in thyroid cancer in previous studies including ours (16,38,39). We consistently show that miR-146b-3p binds to the 3 0 -UTR of NIS (site 3-9 nt), leading to an impaired translation of the protein and subsequently decreasing the iodide uptake of the cells.…”

MECHANISMS IN ENDOCRINOLOGY: MicroRNA in diagnostics and therapy of thyroid cancer

“…Many patients with advanced thyroid cancer do not benefit from the radioiodine therapy due to the reduced expression and function of the Na C /I -symporter (NIS). It was shown that lowered levels of NIS in thyroid tumors are at least in part caused by the overexpression of miR-339 and miR-146b, and inhibition of these microRNAs results in the increased uptake of radioactive iodine by the thyroid cancer cells (68,69,70). Data obtained in the in vitro experiments provided the basis for a number of preclinical studies related to the modulation of microRNAs in PTC, currently performed mainly on mouse models.…”

Inhibition of miR-146b expression increases radioiodine-sensitivity in poorly differential thyroid carcinoma via positively regulating NIS expression

“…Effect of miR-146b dysregulation on NIS activity was verified by luciferase-hNIS-3 0 UTR reporter assay as described before [16]. After seeding for 24 h, FTC-133 cells were transfected with plasmid containing firefly luciferase-hNIS-3 0 UTR (GeneCopoeia), with a Renilla luciferase gene as an internal control, for 14 h using Fugene HD (Promega).…”

“…Down-regulated expression of NIS has been observed in DTC resistance to 131 I therapy [14], on the other hand, increased NIS expression is also reported in follicular cell lines after treated with Trichostatin A (TSA), one of histone deacetylase (HDAC) inhibitors [15]. Currently, NIS-mediated RAIU, the basis for targeted ablation of thyroid cancer remnants, has been proven to be modulated by miR-339-5p through in silico analysis, showing the important role of miR-339-5p in the development or maintenance of thyroid malignancy [16].…”