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Doctoral Thesis
DOI
10.11606/T.42.2011.tde-19032012-154046
Document
Author
Full name
Murilo Vieira Geraldo
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2011
Supervisor
Committee
Kimura, Edna Teruko (President)
Chaves, Maria Luiza Morais Barreto de
Colquhoun, Alison
Martins, Joao Roberto Maciel
Rubio, Ileana Gabriela Sanchez de
Title in Portuguese
Regulação da via de sinalização de TGF-b pelo microRNA miR- 146b-5p no câncer de tiróide.
Keywords in Portuguese
Expressão gênica
Glândula tireóide
Neoplasias da tireóide
Oncogenes
RNA
Transdução de sinal celular
Abstract in Portuguese
MicroRNAs são pequenos RNAs não codificadores de proteínas envolvidos na regulação pós-transcricional da expressão gênica. Análises de expressão em larga escala identificaram aumento da expressão de miR-146b-5p no carcinoma papilífero (PTC), o subtipo mais prevalente do câncer de tiróide. Uma análise in silico apontou SMAD4, um membro da via de sinalização de TGFbeta, como potencial alvo de miR-146b-5p. A via de TGFbeta é uma via inibitória da proliferação da célula folicular, contudo o mecanismo de escape do sinal inibitório de TGFbeta pela célula tumoral tiroideana permanence não esclarecido. A expressão de miR-146b-5p em linhagem normal PCCL3 diminuiu os níveis de SMAD4, conferindo resistência ao sinal anti-proliferativo de TGFbeta e aumentando a proliferação celular. A inibição de miR-146b-5p em linhagens de PTC aumentou os níveis de SMAD4, restaurou a resposta ao sinal anti-proliferativo de TGFbeta, diminuindo a proliferação celular. Os dados obtidos neste trabalho revelam o papel oncogênico de miR-146b-5p como um regulador negativo da via de TGFbeta.
Title in English
Regulation of TGFbeta signaling pathway by microRNA miR-146b-5p in thyroid cancer.
Keywords in English
Cellular signal transduction
Gene expression
Oncogenes
RNA
Thyroid gland
Thyroid neoplasms
Abstract in English
MicroRNAs are small non-coding RNAs involved in post-transcriptional gene regulation. Large-scale analyses revealed that miR-146b-5p is overexpressed in papillary carcinomas (PTC), the most prevalent form of thyroid cancer. A computational analysis indicated SMAD4, an important member of the TGF-b signaling pathway, as a putative target of miR-146b-5p. The TGFbeta pathway is a negative regulator of thyroid follicular cell growth, and the mechanism by which thyroid cancer cells evade its inhibitory signal remains unclear. The overexpression of miR-146b-5p in normal follicular PCCL3 cells decreased SMAD4 levels, conferred resistance to TGFbeta anti-proliferative signal and increased cell proliferation. The specific inhibition of miR-146b-5p in papillary carcinoma cell lines significantly increased SMAD4 levels, restored the TGFbeta signal transduction and decreased cell growth. Altogether, our data confirm the oncogenic role of miR-146b-5p in thyroid follicular cells as a negative regulator of TGFbeta signaling pathway.
 
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Publishing Date
2012-05-25
 
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