Loss of DNA methylation is related to increased expression of miR-21 and miR-146b in papillary thyroid carcinoma

Isabella Maria Dias Payão Ortiz, Mateus Camargo Barros-Filho, Mariana Bisarro Dos Reis, Caroline Moraes Beltrami, Fabio Albuquerque Marchi, Hellen Kuasne, Luísa Matos do Canto, Julia Bette Homem de Mello, Cecilie Abildgaard, Clóvis Antônio Lopes Pinto, Luiz Paulo Kowalski, Silvia Regina Rogatto

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Abstrakt

BACKGROUND: DNA methylation in miRNA genes has been reported as a mechanism that may cause dysregulation of mature miRNAs and consequently impact the gene expression. This mechanism is largely unstudied in papillary thyroid carcinomas (PTC). METHODS: To identify differentially methylated miRNA-encoding genes, we performed global methylation analysis (Illumina 450 K), integrative analysis (TCGA database), data confirmation (pyrosequencing and RT-qPCR), and functional assays. RESULTS: Methylation analysis revealed 27 differentially methylated miRNA genes. The integrative analyses pointed out miR-21 and miR-146b as potentially regulated by methylation (hypomethylation and increased expression). DNA methylation and expression patterns of miR-21 and miR-146b were confirmed as altered, as well as seven of 452 mRNAs targets were down-expressed. The combined methylation and expression levels of miR-21 and miR-146b showed potential to discriminate malignant from benign lesions (91-96% sensitivity and 96-97% specificity). An increased expression of miR-146b due to methylation loss was detected in the TPC1 cell line. The miRNA mimic transfection highlighted putative target mRNAs. CONCLUSIONS: The increased expression of miR-21 and miR-146b due to loss of DNA methylation in PTC resulted in the disruption of the transcription machinery and biological pathways. These miRNAs are potential diagnostic biomarkers, and these findings provide support for future development of targeted therapies.

OriginalsprogEngelsk
Artikelnummer144
TidsskriftClinical Epigenetics (Print)
Vol/bind10
Antal sider13
ISSN1868-7075
DOI
StatusUdgivet - 20. nov. 2018

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