PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation.
Biochim Biophys Acta Mol Basis Dis
; 1864(5 Pt A): 1754-1769, 2018 May.
Article
en En
| MEDLINE
| ID: mdl-29510196
ABSTRACT
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor due to the lack of effective therapeutic drugs. Cancer therapy targeting programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) is of revolutionary. However, the role of intrinsic PD-L1, which determines immune-therapy outcomes, remains largely unclear. Here we demonstrated an oncogenic role of PD-L1 via binding and activating Ras in GBM cells. RNA-sequencing transcriptome data revealed that PD-L1 significantly altered gene expression enriched in cell growth/migration/invasion pathways in human GBM cells. PD-L1 overexpression and knockout or knockdown demonstrated that PD-L1 promoted GBM cell proliferation and migration in vitro and in vivo. Mechanistically, PD-L1 prominently activated epithelial mesenchymal transition (EMT) process in a MEK/Erk- but not PI3K/Akt-dependent manner. Further, we identified intracellular interactions of PD-L1 and H-Ras, which led to Ras/Erk/EMT activation. Finally, we demonstrated that PD-L1 overexpression promoted while knockdown abolished GBM development and invasion in orthotopic GBM models of rodents. Taken together, we found that intracellular PD-L1 confers GBM cell malignancy and aggressiveness via binding Ras and activating the downstream Erk-EMT signaling. Thus, these results shed important insights in improving efficacy of immune therapy for GBM as well as other malignant tumors.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Glioblastoma
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Sistema de Señalización de MAP Quinasas
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Transición Epitelial-Mesenquimal
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Antígeno B7-H1
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Biochim Biophys Acta Mol Basis Dis
Año:
2018
Tipo del documento:
Article
País de afiliación:
China