The cluster of microRNAs miR-17-92 and its targets in thyroid oncogenesis: the influence of BRAFT1799A and iodine

Author(s)

Cesar Seigi Fuziwara

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2014-08-29

Examining board members

Edna Teruko Kimura; Robson Francisco Carvalho; Patricia Pereira Coltri; Rui Monteiro de Barros Maciel; Fernanda Ortis

• Advisor: Edna Teruko Kimura

Abstract

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. (AU)