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

• Published in: Clinical epigenetics Vol. 10; no. 1; p. 144
• Main Authors: Ortiz, Isabella Maria Dias Payão, Barros-Filho, Mateus Camargo, Dos Reis, Mariana Bisarro, Beltrami, Caroline Moraes, Marchi, Fabio Albuquerque, Kuasne, Hellen, do Canto, Luísa Matos, de Mello, Julia Bette Homem, Abildgaard, Cecilie, Pinto, Clóvis Antônio Lopes, Kowalski, Luiz Paulo, Rogatto, Silvia Regina
• Format: Journal Article
• Language: English
• Published: Germany BioMed Central Ltd 20.11.2018; BioMed Central; BMC
• Subjects: Biomarkers; Biomarkers, Tumor - genetics; Breast cancer; Carcinoma; Cell cycle; Cell Line, Tumor; Data processing; Deoxyribonucleic acid; DNA; DNA Methylation; Epigenetics; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genomes; Humans; Methylation; MicroRNA; MicroRNAs; MicroRNAs - genetics; miR-146b; miR-21; miRNA; Mutation; Papillary thyroid; Papillary thyroid carcinoma; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; Sequence Analysis, DNA; Thyroid; Thyroid cancer; Thyroid Cancer, Papillary - diagnosis; Thyroid Cancer, Papillary - genetics; Thyroid Neoplasms - diagnosis; Thyroid Neoplasms - genetics; Transcription; Transfection; Up-Regulation; DNA methylation; microRNA; miR-146b; Carcinoma; miR-21; Papillary thyroid
• ISSN: 1868-7075; 1868-7083; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-018-0579-8

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). 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. 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. 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.