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Doctoral Thesis
DOI
10.11606/T.42.2014.tde-19112014-162309
Document
Author
Full name
Cesar Seigi Fuziwara
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2014
Supervisor
Committee
Kimura, Edna Teruko (President)
Carvalho, Robson Francisco
Coltri, Patricia Pereira
Maciel, Rui Monteiro de Barros
Ortis, Fernanda
Title in Portuguese
O cluster de microRNAs miR-17-92 e seus alvos na oncogênese tiroidiana: influência de BRAFT1799A e de iodo.
Keywords in Portuguese
BRAF
Câncer de tiroide
Iodo
MicroRNA
miR-17-92
Smad4
Abstract in Portuguese
O excesso de iodo inibe a proliferação celular e secreção hormonal, enquanto retarda os efeitos oncogênicos da ativação de RET/PTC3 na célula folicular tiroidiana. A mutação BRAF (T1799A) é a mais prevalente no câncer de tiroide, e modelo transgênico desenvolve câncer que progride para histotipo agressivo. Altos níveis de microRNAs (miRNAs) do cluster miR-17-92 estão associados a histotipos agressivos de câncer de tiroide e modulam a tradução de mRNAs alvo componentes de vias de sinalização oncogênicas. Neste estudo, avaliamos a influência da alta dose de iodo sobre miRNAs frente ativação do oncogene BRAF e seu efeito na biologia da célula folicular tiroidiana. A indução de BRAFT1799A ativa uma robusta expressão de miR-17-92 enquanto alta dose de iodo bloqueia este efeito na célula tiroidiana. miR-19 inibe a tradução de Smad4 e bloqueia a transdução do sinal de TGFb, efeito revertido pelo iodo. O iodo interfere na expressão de miR-17-92 por bloquear ativação da sinalização Notch induzida por BRAF. Estes resultados indicam que o iodo protege a célula folicular tiroidiana durante a indução de BRAFT1799A, revertendo a ativação dos miRNAs oncogênicos do cluster miR-17-92 e restaurando os níveis protéicos de Smad4 por interferir na via de sinalização Notch.
Title in English
The cluster of microRNAs miR-17-92 and its targets in thyroid oncogenesis: the influence of BRAFT1799A and iodine
Keywords in English
BRAF
Iodine
MicroRNA
miR-17-92
Smad4
Thyroid cancer
Abstract in English
Iodine excess blocks cell proliferation and inhibits hormone synthesis, while delays oncogenic effects of RET/PTC3 activation in thyroid follicular cells. BRAF mutation (T1799A) is the most prevalent genetic alteration in thyroid cancer, and transgenic mice model for BRAF develops thyroid cancer that progress to aggressive histotypes. High levels of microRNAs (miRNAs) of miR-17-92 cluster are associated to aggressive thyroid cancer and modulate translation of target mRNAs in oncogenic signaling pathways. In this study, we evaluated the influence of high dose iodine in miRNAs under BRAF oncogene activation, and its effects in thyroid follicular cell biology. BRAF induction induces high expression of miR-17-92 while high dose iodine blocks this effect in thyroid follicular cells. miR-19 inhibits Smad4 translation and impairs TGFb signaling transduction, effect reverted by iodine. Iodine modulates miR-17-92 expression by interfering in BRAF-induced Notch signaling activation. These results indicate that iodine protects thyroid follicular cell during BRAF induction, reverting oncogenic miR-17-92 activation and restoring protein levels of Smad4 by Notch signaling modulation.
 
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Release Date
2016-11-26
Publishing Date
2014-11-27
 
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