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Doctoral Thesis
DOI
10.11606/T.42.2018.tde-26092018-102850
Document
Author
Full name
Rebeca Piatniczka Iglesia
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2017
Supervisor
Committee
Lopes, Marilene Hohmuth (President)
Câmara, Niels Olsen Saraiva
Colquhoun, Alison
Costa, Erico Tosoni
Engler, Silvya Stuchi Maria
Title in Portuguese
Estudo da interação entre PrPC e STI1/HOP na biologia de células-tronco de glioblastoma humano in vivo.
Keywords in Portuguese
Autorrenovação
Células-tronco de glioblastoma
Glioblastoma
Heat shock organizing protein
Proliferação
Proteína prion celular
Abstract in Portuguese
O GBM é o tipo mais agressivo de glioma, apresentando células indiferenciadas (CTGs), responsáveis pela proliferação, invasão e recidiva tumoral. Avaliamos o papel da proteína PrPC e seu ligante HOP na proliferação e autorrenovação de CTGs. Cultivamos linhagens de GBM humano em neuroesferas e geramos populações knockdown para PrPC e HOP. Observamos co-localização de PrPC e CD133 na superfície e sua internalização conjunta estimulada por cobre, sugerindo recrutamento de CD133 mediado por PrPC. O silenciamento de PrPC reduz a expressão de marcadores de células-tronco e autorrenovação, diminui a expressão de proteínas de adesão e afeta a migração celular. O silenciamento de HOP reduz a proliferação, recuperada com o tratamento com HOP em células PrPC+. A capacidade tumorigênica e proliferativa de neuroesferas knockdown para PrPC e/ou HOP in vivo é reduzida. Finalmente, um peptídeo de HOP que bloqueia a interação com PrPC inibe a proliferação e autorrenovação em células PrPC+, indicando potencial do complexo PrPC-HOP como alvo para terapias contra o GBM.
Title in English
Role of PrPC and STI1/HOP in human glioblastoma stem cells biology in vivo.
Keywords in English
Cellular prion protein
Glioblastoma
Glioblastoma stem cells
Heat shock organizing protein
Proliferation
Self-renewal
Abstract in English
GBM is the most aggressive type of glioma, presenting undifferentiated cells (GSCs), responsible for proliferation, invasion and tumor recurrence. We evaluated the role of the PrPC and its ligand HOP in the proliferation and self-renewal of GSCs. We cultured human GBM lineages in neurospheres and generated knockdown populations for PrPC and HOP. We observed co-localization of PrPC and CD133 on the surface and their co-stimulated copper internalization, suggesting PrPC-mediated recruitment of CD133. PrPC silencing reduces the expression of stem cell markers and self-renewal, decreases adhesion proteins expression, and affects cell migration. HOP silencing reduces proliferation, recovered with HOP treatment in PrPC+ cells. The tumorigenic and proliferative capacity of neurospheres PrPC and/or HOP knockdown in vivo is decreased. Finally, a HOP peptide which blocks PrPC-HOP interaction inhibits proliferation and self-renewal in PrPC+ cells, indicating PrPC-HOP complex potential as a target for therapies against GBM.
 
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Release Date
2020-09-25
Publishing Date
2018-09-26
 
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