Bone marrow fibroblasts overexpress miR-27b and miR-214 in step with multiple myeloma progression, dependent on tumour cell-derived exosomes.
J Pathol
; 247(2): 241-253, 2019 02.
Article
em En
| MEDLINE
| ID: mdl-30357841
ABSTRACT
Aberrant microRNA (miR) expression has an important role in tumour progression, but its involvement in bone marrow fibroblasts of multiple myeloma patients remains undefined. We demonstrate that a specific miR profile in bone marrow fibroblasts parallels the transition from monoclonal gammopathy of undetermined significance (MGUS) to myeloma. Overexpression of miR-27b-3p and miR-214-3p triggers proliferation and apoptosis resistance in myeloma fibroblasts via the FBXW7 and PTEN/AKT/GSK3 pathways, respectively. Transient transfection of miR-27b-3p and miR-214-3p inhibitors demonstrates a cooperation between these two miRNAs in the expression of the anti-apoptotic factor MCL1, suggesting that miR-27b-3p and miR-214-3p negatively regulate myeloma fibroblast apoptosis. Furthermore, myeloma cells modulate miR-27b-3p and miR-214-3p expression in fibroblasts through the release of exosomes. Indeed, tumour cell-derived exosomes induce an overexpression of both miRNAs in MGUS fibroblasts not through a simple transfer mechanism but by de novo synthesis triggered by the transfer of exosomal WWC2 protein that regulates the Hippo pathway. Increased levels of miR-27b-3p and miR-214-3p in MGUS fibroblasts co-cultured with myeloma cell-derived exosomes enhance the expression of fibroblast activation markers αSMA and FAP. These data show that the MGUS-to-myeloma transition entails an aberrant miRNA profile in marrow fibroblasts and highlight a key role of myeloma cells in modifying the bone marrow microenvironment by reprogramming the marrow fibroblasts' behaviour. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Gamopatia Monoclonal de Significância Indeterminada
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Células da Medula Óssea
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MicroRNAs
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Exossomos
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Fibroblastos
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Mieloma Múltiplo
Limite:
Aged80
Idioma:
En
Revista:
J Pathol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Itália
País de publicação:
ENGLAND
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ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
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REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM