Estudo da interação entre PrPC e STI1/HOP na biologia de células-tronco de glioblastoma humano in vivo.

Iglesia, Rebeca Piatniczka

doi:10.11606/T.42.2018.tde-26092018-102850

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DOI

https://doi.org/10.11606/T.42.2018.tde-26092018-102850

Document

Doctoral Thesis

Author

Iglesia, Rebeca Piatniczka (Catálogo USP)

Full name

Rebeca Piatniczka Iglesia

Institute/School/College

Instituto de Ciências Biomédicas

Knowledge Area

Cell and Tissue Biology

Date of Defense

2017-04-10

Published

São Paulo, 2017

Supervisor

Lopes, Marilene Hohmuth (Catálogo USP)
Santos, Tiago Góss dos - (Co-supervisor) (Catálogo USP)

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 PrP^Ce 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 PrP^C e seu ligante HOP na proliferação e autorrenovação de CTGs. Cultivamos linhagens de GBM humano em neuroesferas e geramos populações knockdown para PrP^C e HOP. Observamos co-localização de PrP^C e CD133 na superfície e sua internalização conjunta estimulada por cobre, sugerindo recrutamento de CD133 mediado por PrP^C. O silenciamento de PrP^C 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 PrP^C+. A capacidade tumorigênica e proliferativa de neuroesferas knockdown para PrP^C e/ou HOP in vivo é reduzida. Finalmente, um peptídeo de HOP que bloqueia a interação com PrP^C inibe a proliferação e autorrenovação em células PrP^C+, indicando potencial do complexo PrP^C-HOP como alvo para terapias contra o GBM.

Title in English

Role of PrP^C 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 PrP^C and its ligand HOP in the proliferation and self-renewal of GSCs. We cultured human GBM lineages in neurospheres and generated knockdown populations for PrP^C and HOP. We observed co-localization of PrP^C and CD133 on the surface and their co-stimulated copper internalization, suggesting PrP^C-mediated recruitment of CD133. PrP^C 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 PrP^C+ cells. The tumorigenic and proliferative capacity of neurospheres PrP^C and/or HOP knockdown in vivo is decreased. Finally, a HOP peptide which blocks PrP^C-HOP interaction inhibits proliferation and self-renewal in PrP^C+ cells, indicating PrP^C-HOP complex potential as a target for therapies against GBM.

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Publishing Date

2018-09-26

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