Lakshmanan Aparna, Wojcicka Anna, Kotlarek Marta, Zhang Xiaoli, Jazdzewski Krystian, Jhiang Sissy M
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.
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.
Endocr Relat Cancer. 2015 Feb;22(1):11-21. doi: 10.1530/ERC-14-0439. Epub 2014 Nov 17.
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.
钠/碘同向转运体（NIS）介导的放射性碘摄取（RAIU）是甲状腺癌残留组织靶向消融的基础。然而，许多甲状腺癌患者的NIS表达/功能降低，因此无法从放射性碘治疗中获益。微小RNA（miR）已成为许多疾病中一个有前景的治疗靶点；然而，miR在NIS介导的RAIU中的作用尚未得到研究。通过计算机分析来鉴定可能与人NIS（hNIS）的3'非翻译区（3'UTR）结合的miR。排名靠前的候选miR-339-5p直接与hNIS的3'UTR结合。在表达外源性hNIS的HEK293细胞中，miR-339-5p过表达降低了NIS介导的RAIU，降低了NIS mRNA水平，并且在全反式维甲酸/氢化可的松（tRA/H）处理的MCF-7人乳腺癌细胞以及促甲状腺素刺激的PCCl3大鼠甲状腺细胞中降低了RAIU。进行了Nanostring nCounter大鼠miR表达分析，以鉴定已知可调节PCCl3细胞中RAIU的转化生长因子β（TGFβ）、Akti-1/2或17-AAG所失调的miR。在鉴定出的38个miR中，有18个在人类中保守。这18个miR中的一个，即miR-195，被预测与hNIS的3'UTR结合，其过表达降低了tRA/H处理的MCF-7细胞中的RAIU。在大多数乳头状甲状腺癌（PTC）中，miR-339-5p略有增加，但在PTC中miR-195显著降低。有趣的是，这18个miR的表达谱可用于区分大多数PTC与非恶性甲状腺组织。据我们所知，这是第一份证明hNIS介导的RAIU可被miR调节，并且相同的miR可能也在甲状腺恶性肿瘤的发生或维持中起作用的报告。因此，miR可能成为阻止甲状腺癌进展并提高放射性碘治疗疗效的新靶点。
