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

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Dias Payao Ortiz, Isabella Maria ^[1] ; Barros-Filho, Mateus Camargo ^[1] ; dos Reis, Mariana Bisarro ^[1] ; Beltrami, Caroline Moraes ^[1] ; Marchi, Fabio Albuquerque ^[1] ; Kuasne, Hellen ^[1] ; do Canto, Luisa Matos ^{[1, 2]} ; Homem de Mello, Julia Bette ^[1] ; Abildgaard, Cecilie ^[2] ; Lopes Pinto, Clovis Antonio ^[3] ; Kowalski, Luiz Paulo ^[4] ; Rogatto, Silvia Regina ^[2]

Afiliação do(s) autor(es)

^[1] AC Camargo Canc Ctr, Int Res Ctr CIPE, Tagua St 440, BR-01508010 Sao Paulo - Brazil

^[2] Univ Southern Denmark, Inst Reg Hlth Res, Dept Clin Genet, Vejle Hosp, Beriderbakken 4, DK-7100 Vejle - Denmark

^[3] AC Camargo Canc Ctr, Dept Pathol, Prof Antonio Prudente St 211, BR-01509900 Sao Paulo - Brazil

^[4] AC Camargo Canc Ctr, Dept Head & Neck Surg & Otorhinolaryngol, Prof Antonio Prudente St 211, BR-01509900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CLINICAL EPIGENETICS; v. 10, NOV 20 2018.
• Citações Web of Science: 5

Resumo

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. (AU)

• Processo FAPESP: 15/17707-5 - Desenvolvimento de métodos moleculares úteis para o diagnóstico diferencial de nódulos da tireóide
• Beneficiário: Mateus de Camargo Barros Filho
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/20748-5 - Marcadores diagnósticos e prognósticos aplicáveis na prática clínica para pacientes com nódulos tireoidianos: validação de achados prévios e estudos funcionais
• Beneficiário: Silvia Regina Rogatto
• Modalidade de apoio: Auxílio à Pesquisa - Regular