title: 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 thyrotropin-stimulated 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 38 miRs 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 in most 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.
authors.affiliation: Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Lakshmanan
authors.affiliation: Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Wojcicka
authors.affiliation: Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Kotlarek
authors.affiliation: Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA jhiang.1@osu.edu krystian.jazdzewski@wum.edu.pl.
authors.forename: Krystian
authors.initials: K
authors.lastname: Jazdzewski
authors.affiliation: Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA Department of Physiology and Cell BiologyMolecularCellular and Developmental Biology Graduate Program, The Ohio State University, 1645 Neil Avenue, 304 Hamilton Hall, Columbus, Ohio 43210, USAGenomic MedicineDepartment of General, Transplant, and Liver Surgery, Medical University of Warsaw, Zwirki i Wigury 61, 02-091 Warsaw, PolLaboratory of Human Cancer GeneticsCentre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, PolCenter for BiostatisticsThe Ohio State University, Columbus, Ohio, USA jhiang.1@osu.edu krystian.jazdzewski@wum.edu.pl.
authors.forename: Sissy M
authors.initials: SM
authors.lastname: Jhiang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001943:Breast Neoplasms; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy*; D002291:Carcinoma, Papillary; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D027981:Symporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy*; D000099209:Sodium-Iodide Symporters
chemical_list: D020413:3' Untranslated Regions; D007457:Iodine Radioisotopes; D035683:MicroRNAs; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C543820:MIRN339 microRNA, human
keywords: NIS; microRNA-339-5p; papillary thyroid carcinoma; radioiodide uptake