The miR-146b-3p/PAX8/NIS Regulatory Circuit Modulates the Differentiation Phenotype and Function of Thyroid Cells during Carcinogenesis.
The presence of differentiated thyroid cells in thyroid cancer is critical for the antitumor response to radioactive iodide treatment, and loss of the differentiated phenotype is a key hallmark of iodide-refractory metastatic disease. The role of microRNAs (miRNA) in fine-tuning gene expression has become a major regulatory mechanism by which developmental and pathologic processes occur. In this study, we performed next-generation sequencing and expression analysis of eight papillary thyroid carcinomas (PTC) to comprehensively characterize miRNAs involved in loss of differentiation. We found that only a small set of abundant miRNAs is differentially expressed between PTC tissue and normal tissue from the same patient. In addition, we integrated computational prediction of potential targets and mRNA sequencing and identified a master miRNA regulatory network involved in essential biologic processes such as thyroid differentiation. Both mature products of mir-146b (miR-146b-5p and -3p) were among the most abundantly expressed miRNAs in tumors. Specifically, we found that miR-146b-3p binds to the 3'-untranslated region of PAX8 and sodium/iodide symporter (NIS), leading to impaired protein translation and a subsequent reduction in iodide uptake. Furthermore, our findings show that miR-146b and PAX8 regulate each other and share common target genes, thus highlighting a novel regulatory circuit that governs the differentiated phenotype of PTC. In conclusion, our study has uncovered the existence of a miR-146b-3p/PAX8/NIS regulatory circuit that may be exploited therapeutically to modulate thyroid cell differentiation and iodide uptake for improved treatment of advanced thyroid cancer.
Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain. Servicio de Endocrinología y Nutrición, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain. Servicio de Endocrinología Hospital Universitario de Móstoles, Madrid, Spain.
Garcilaso
G
Riesco-Eizaguirre
Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
León
L
Wert-Lamas
Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain. Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Javier
J
Perales-Patón
Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
Ana
A
Sastre-Perona
Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
Lara P
LP
Fernández
Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain. psantisteban@iib.uam.es.
Pilar
P
Santisteban
D020413:3' Untranslated Regions; D001692:Biological Transport; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007454:Iodides / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D012334:RNA, Neoplasm / Q000502:physiology*; D027981:Symporters / Q000502:physiology*; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D000099209:Sodium-Iodide Symporters
D020413:3' Untranslated Regions; D007454:Iodides; D035683:MicroRNAs; D009363:Neoplasm Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D012313:RNA; D012334:RNA, Neoplasm; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C542542:MIRN146 microRNA, human; C083325:PAX8 protein, human; C039919:RNA, recombinant