• JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
 
  Bookmark and Share
 
 
Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2020.tde-11032020-124505
Document
Author
Full name
Natalia Garcia
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Carvalho, Kátia Cândido (President)
Cunha, Isabela Werneck da
Júnior, José Maria Soares
Shinjo, Sueli Mieko Oba
Title in Portuguese
Inibidores da via de sinalização do Sonic hedgehog: avaliação de seus efeitos in vitro em leiomioma e leiomiossarcoma uterinos
Keywords in Portuguese
Leiomioma
Leiomiossarcoma
Neoplasias uterinas
Proteínas hedgehog
Tratamento farmacológico
Abstract in Portuguese
O leiomioma (LM) e o leiomiossarcoma (LMS) são tumores de origem mesenquimal. O LM uterino é um tumor benigno comumente encontrado nas mulheres em idade reprodutiva, enquanto os LMS são tumores raros que representam 7% de todos os sarcomas de tecidos moles, e cerca de 40% dos sarcomas do útero. Essas neoplasias apresentam comportamento clínico variável e seu diagnóstico definitivo ocorre somente após cirurgia. Estudos demonstram que a ativação aberrante da via de sinalização do Sonic hedgehog (SHH) se relaciona ao desenvolvimento de vários tipos de cânceres, uma vez que desempenha papel importante na proliferação e diferenciação celular. Em trabalho anterior do grupo, as proteínas SMO e GLI1 mostraram-se hiperexpressas em LMS, seguido pelos LMs e ausentes no miométrio (MM) adjacente. Com base nesses achados, nosso objetivo aqui foi avaliar, in vitro, a ação de inibidores de SMO e GLI1, e consequentemente da via do SHH, em LM e LMS. Para tanto, linhagens celulares de MM, LM e LMS foram avaliadas quanto à expressão basal de componentes dessa via e de seus principais alvos. Os efeitos dos tratamentos com inibidores de SMO (GDC0449 e LDE225) e GLI (Gant58 e Gant61) na expressão dos genes e proteínas de interesse foram avaliados por q-PCR e Western Blot, respectivamente. Enquanto que seus efeitos no comportamento celular foram avaliados por ensaios de proliferação, migração, invasão e apoptose. Nossos resultados mostraram que, dentre os inibidores testados, LDE225 e Gant61 foram os mais promissores. Ambos apresentaram efeito inibitório na proliferação das células de LMS, induziram perda na expressão de SMO, GLI1, GLI2 e GLI3, e inibiram os mecanismos de migração e invasão, além de aumentar o índice apoptótico. Esses efeitos, em conjunto, sugerem o potencial uso desses fármacos para terapia alvo específica nos LMS, via bloqueio da via do SHH
Title in English
Sonic hedgehog signaling pathway inhibitors: evaluation of in vitro effects on uterine leiomyomas and leiomyosarcomas
Keywords in English
Drug therapy
Hedgehog proteins
Leiomyoma
Leiomyosarcoma
Uterine neoplasm
Abstract in English
Leiomyoma (LM) and leiomyosarcoma (LMS) are uterine mesenchymal tumors. Uterine LM is a benign tumor commonly affecting women at reproductive age whereas LMS are rare tumors represent 7% of all soft tissue sarcomas and 40% of all uterine sarcomas. These neoplasms have variable clinical behavior and their definitive diagnosis occurs only after surgery. Several studies have shown that aberrant activation of the Sonic hedgehog (SHH) signaling pathway plays an important role in cell proliferation and differentiation. In a previous study of our group, we found a hyperexpression of SMO and GLI1 proteins in LMS, compared to LM and no expression in myometrium (MM). The aim of this work was to evaluate, in vitro, inhibitors of the Sonic hedgehog signaling pathway in LM and LMS. For this purpose, MM, LM and LMS cell lines were evaluated for basal expressions of SHH pathway components and major targets. The effect of SMO (GDC0449 and LDE225) and GLI (Gant58 and Gant61) inhibitors in gene and protein expression levels were determined by q-PCR and Western Blot analysis respectively. Proliferation, migration, invasion and apoptosis assays were also performed. Our results showed that among the inhibitors tested, LDE225 and Gant61 were the most promising. Both had an inhibitory effect on LMS cell proliferation, they induced inhibition of SMO, GLI1, GLI2 and GLI3 expression, inhibited migration and invasion mechanisms, and increased apoptotic index. These effects together suggest the potential use of these drugs for specific target therapy in LMS via SHH blockade
 
WARNING - Viewing this document is conditioned on your acceptance of the following terms of use:
This document is only for private use for research and teaching activities. Reproduction for commercial use is forbidden. This rights cover the whole data about this document as well as its contents. Any uses or copies of this document in whole or in part must include the author's name.
Publishing Date
2020-03-11
 
WARNING: Learn what derived works are clicking here.
All rights of the thesis/dissertation are from the authors
CeTI-SC/STI
Digital Library of Theses and Dissertations of USP. Copyright © 2001-2022. All rights reserved.